Episode 11 – Chris Masterjohn on cholesterol & heart disease (Part 1)

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This week we’re glad to welcome Chris Masterjohn to the show. Chris is currently pursuing a PhD in Nutritional Sciences with a concentration in Biochemical and Molecular Nutrition at the University of Connecticut. He writes a blog called The Daily Lipid and is also a frequent contributor on the Weston A. Price Foundation’s blog.

I consider Chris to be one of the foremost experts on the topic of cholesterol and its relationship to heart disease. In this episode, we discuss (among other things):

  • the history of the cholesterol-heart disease connection
  • misconceptions around diet vs. lipid hypothesis
  • finding middle ground between cholesterol skeptics and proponents of the lipid hypothesis
  • the LDL receptor and familial hypercholesterolemia and what they can tell us about cholesterol and CHD in normal populations

We didn’t get to any questions this time around, but Chris has graciously offered to come back and do an entire episode devoted to Q&A in the future – so look out for that!

Play

Danny Roddy: This turned out to be a longer show than we anticipated. To make it easier for those of you that are time challenged, the first hour is an extensive review of the theory that cholesterol causes heart disease. If you read Chris Masterjohn’s work regularly and you’re already familiar with his material, you might wish to skip forward to the sixty minute mark, where we begin to discuss the role of oxidized LDL and heart disease, living with familial hypercholesterolemia, and other advanced topics.

Hello everyone and welcome to the Healthy Skeptic podcast. My name is Danny Roddy and with me is Chris Kresser, health detective and creator of thehealthyskeptic.org, a blog challenging mainstream myths about nutrition and health. Chris, how are you doin’ buddy?

Chris Kresser: I’m doin’ great. Oh yeah there’s two Chris’. We got Chris Masterjohn on the line too. Why don’t you tell us how you’re doing first, Chris.

Chris Masterjohn: I’m doin’ pretty well Chris, how you doin’?

Chris Kresser: Good, good. I’m eagerly awaiting the baby at this point, I think something like 8 weeks left, my wife looks like she’s swallowed a basketball. In the most flattering, complementary possible way. She’s radiant and beautiful and it’s pretty exciting as the time gets closer and closer I’m just getting more and more excited. We havn’t even had an ultrasound so we have no idea whether it’s gonna be a boy or girl, or what little being is gonna come into the world and change our lives forever pretty soon.

Danny Roddy: You’re kickin’ it old school.

Chris Kresser: Kickin’ it old school, yeah. Evolutionary style, paleo style pregnancy. So how about you Danny?

Danny Roddy: Uh, honestly I just got out of school so I’m lazing it up really hard and I’m not doing anything.

Chris Kresser: Tanning on the sidewalk?

Danny Roddy: Always, always.

Chris Kresser: We are really excited to have Chris Masterjohn here. For those of you who don’t already, for the two or three people out there who don’t already know who he is, Chris is the creator and maintainer of cholesterolandhealth.com, which is a website dedicated to extolling the benefits of traditional, nutrient dense, cholesterol rich foods, and to elucidating the many fascinating roles cholesterol plays within the body. And cholesterolandhealth.com is also home to his excellent blog, the daily lipid, which is a must-read if you’re not already subscribed to it. Chris is a frequent contributor to wise traditions, which is the quarterly journal of the Weston A. Price Foundation, which I’ve talked about of course a lot on the show. And he’s a regular speaker at the annual wise traditions conference and writes a second blog on the Weston A. Price Foundation’s website called mother nature obeyed. Chris is a doctoral candidate in nutritional sciences at the University of Connecticut, which means he’s very smart. And he has authored three peer-reviewed publications including a hypothesis on the molecular mechanism of vitamin D toxicity, published in medical hypotheses, a letter to the editor published in the Journal of American Cardiology challenging the conclusions of a study claiming to show adverse effects of eating coconut oil, which we know is a very healthy food. And a letter to the editor published in the American Heart Journal arguing that drugs used to raise HDL cholesterol should not be considered safe until their potential adverse effects on vitamin E metabolism had been studied. And he’s also recently authored Human Study on the Effects of Vitamin E on Sugar Metabolism that’s been accepted for publication in the Journal of Nutritional Biochemistry, as well as a review on non-alcoholic fatty liver disease accepted for publication in Nutrition Reviews. Chris plans on graduating with his Doctorate in the summer, congratulations Chris, that must be exciting.

Chris Masterjohn: Thank you so much, congratulations to you, you’ve got a lot going on too.

Chris Kresser: Yeah everybody’s busy… So today, we’re gonna talk about cholesterol and this is something I’ve wanted to revisit for a long time now. I actually started my blog three or four years ago now, with some articles about cholesterol, it’s kind of how I got into this whole thing. I’d have to say my understanding has evolved quite a bit since I wrote those original articles and even since I recorded the videos, ‘I have high cholesterol and I don’t care’, which you can find on my site. And Chris, among other people but I would say especially Chris has been instrumental in the evolution of my understanding of cholesterol and so I wanted to have him on the show so we could talk about it and the idea here is to get sort of a 21st century view of what we know about cholesterol and especially its relationship to heart disease. There’s so much misinformation out there on both sides really, and we’re gonna talk a little bit about that. You’ve got one group that is still out there saying that high cholesterol itself is the cause of heart disease, and you’ve got another group, the cholesterol skeptics, who say that cholesterol makes no difference at all, doesn’t matter, it’s not reflective of anything in the body and you don’t have to worry about cholesterol, and Chris is gonna tell us why both of those arguments are not correct. Chris again, we’re excited to have you here thanks for coming on the show.

Chris Masterjohn: Thank you so much for having me, I’m excited to be here as well.

Chris Kresser: Great, so let’s start with a kind of 101 elementary topic but it’s one that I think still a lot of people especially in the mainstream don’t really understand, which is the screwed up nomenclature that’s used to talk about cholesterol. Someone goes to the doctor and they come back and they tell their wife, I’ve got high cholesterol. But what they’re referring to as cholesterol is not is not actually cholesterol is it Chris?

Chris Masterjohn: Alright Chris that’s a great question. So the only way to really describe this nomenclature is screwed up or at least very confusing. A lot of people when they go to get their cholesterol tested their doctor tells them your LDL is such and such, your HDL is such and such. And what they’re actually referring to by LDL and HDL are lipoproteins. Low-density lipoprotein and high-density lipoprotein. But the numbers that you’re getting are not your LDL and your HDL, they’re your LDL cholesterol and your HDL cholesterol. So the numbers that you’re getting are the amount of cholesterol that is contained within each lipoprotein. But the lipoprotein itself is not cholesterol it’s basically a carrier or transporter. So in order to understand these two things we should really look at what are the roles that cholesterol plays in the body and what are the roles that these lipoproteins play. And what we see is we get two very different answers. If you wanna understand what cholesterol does in the body, the best way to look at that is to look at cholesterol deficiency. And cholesterol deficiency can be seen in what’s referred to as Smith-Lemli-Opitz Syndrome, SLOS, and this is a genetic deficiency in cholesterol production. So if we look at the type of symptoms of this genetic deficiency in cholesterol, we can start to understand the types of things that cholesterol does. In most cases, someone who’s born with Smith-Lemli-Opitz, someone who’s conceived, most conceptions with Smith-Lemli-Opitz Syndrome are spontaneously aborted. So the first thing we can see is that cholesterol is essential to fertility, to carrying on a normal pregnancy, and to basic life and growth of a human being. But in the rare cases where someone actually is born with this disorder, they have all kinds of facial and skeletal abnormalities. They can have mental retardation, autism, hyperactivity disorders, attention deficit disorders, visual disfunction, endocrine disfunction, serious digestive problems, and self-injurious and aggressive behavior. So you can start to see that cholesterol is basically affecting everything in the body. And in fact the usual treatment for this syndrome has been a diet rich in cream and egg yolks, which are rich in naturally occurring cholesterol. But somewhat recently the FDA approved a pharmaceutical grade cholesterol supplement to treat the disorder. Because these people’s digestive system is so bad that they can’t absorb cholesterol from food very well, because cholesterol is necessary for digestion. So basically what is cholesterol do in the body? Well it’s an essential component of our cell membranes where it helps maintain them the consistency of olive oil, not too fluid, not too stiff. It’s very important to the brain, our brain is 2% of our body weight but it contains 25% of our cholesterol. When we go to sleep at night our brain makes more cholesterol, that’s part of why sleep is good for us. And cholesterol is the limiting factor for the formation of connections between neurons. So we can learn things and remember things. Cholesterol is necessary for the production of all the steroid hormones, so those regulate our blood sugar, our mineral metabolism, and all our sex hormones. And it’s necessary for the production of bile acids, which is necessary for digestion. And a closely related compound 7-dehydrocholesterol is needed for vitamin D synthesis. So this is cholesterol.

Chris Kresser: Yeah, it’s a shame how few people are aware of this because the common mentality, not in the paleo world but in the mainstream world, is the lower your cholesterol is, the better. If you could just get it down to zero you’d be in great shape.

Chris Masterjohn: Yeah and you can see exactly what happens when you get your cholesterol down to practically zero by looking at these rare genetic cases and see it’s actually a disastrous thing. I’d rather grow up and get heart disease when I’m 55 then have to go through this when I’m a little child. No one would wanna wish that upon another child. We certainly wanna prevent heart disease but the last thing we wanna do is attempt to prevent it by getting cholesterol right down to zero. When you get your lipoproteins tested you’re really looking at something very different. People say there’s good cholesterol and bad cholesterol. But that one cholesterol compound is the one I was just talking about that does all of those things in the body. There are different types of lipoproteins, but lipoproteins carry cholesterol, they aren’t a type of cholesterol. In your lipoproteins, you basically make a few different kinds, but they can roughly be divided into LDL and LDL-like lipoproteins and HDL. Basically the intestines and the liver are secreting these lipoproteins in order to transport cholesterol, fats, and fat soluble vitamins, such as vitamin A,D,E, and K, coenzyme Q-10 and so on, to the many other cells in the body and to make sure that these nutrients are reaching those cells. And in some cases for example HDL seems to be able to have a very specific role in delivering vitamin E to the blood vessels, or cholesterol to the brain in some cases. So these are transporters, and their roles are primarily in the blood, and they’re primarily playing positive roles as well by delivering these nutrients to our cells. If our cells don’t get these nutrients we get all kinds of other deficiency symptoms. And it’s also possible that lipoproteins play some role in the immune system as well.

Chris Kresser: Right. So just broadly condemning LDL as bad is just as silly as saying cholesterol itself is bad.

Chris Masterjohn: Right if you don’t have the LDL particle you’re not going to get those nutrients to where they need to be, that’s what LDL is all about.

Chris Kresser: So as long as we’re talking about nomenclature here, let’s talk about another common misunderstanding which is conflating the diet-heart and the lipid hypotheses. Why don’t you tell us what each of those is, and then we can get into whether either or both of them are true.

Chris Masterjohn: Okay well, both of these terminologies are unfortunate, because in either case you can say well what diet, or what lipid. The diet-heart hypothesis sounds like it’s saying diet plays a role in heart disease, of course diet plays a role in heart disease. Diet plays a role in basically every condition of health and disease. So there must be some sense in which some diet-heart hypothesis is true. But to understand how these are used in science, we should at least acknowledge the use of this terminology in its historical context. And in its historical context the diet-heart hypothesis refers to the idea that saturated fat and maybe cholesterol in the diet or in some cases total fat, leads to an increased level of cholesterol in the blood, and that causes heart disease. This is dependent on, but nevertheless distinct from the lipid hypothesis. The lipid hypothesis says that cholesterol levels in the blood, regardless of what causes them to go up or down, are what determines our risk for heart disease, Now it’s incredibly important to distinguish between these two hypotheses, because we really aren’t going to be able to understand the truth about heart disease unless we are able to make the finer distinction. And in fact conflating these two hypotheses is what led to the condemnation of bacon, butter, and eggs in 1984 when the coronary primary prevention trial showed that a cholesterol lowering drug reduced the risk for heart disease and then Time magazine came along and said now it’s proven that bacon, butter, and eggs cause heart disease. But of course there were no bacon, butter, or eggs in that trial. And if we were thinking more scientifically and able to shoot back, no you were testing a drug, we wouldn’t have gotten into this mess in the first place with all of this ridiculous mythology about diet.

Chris Kresser: That’s the famous Time magazine cover with the two fried eggs and the bacon frowny face right. So let’s go back to the diet-heart hypothesis, the idea that eating saturate fat raises cholesterol levels in the blood, a, and b that eating saturated fat causes heart disease. Are either of those true?

Chris Masterjohn: It depends what data set you wanna look at in terms of whether saturated fat increases cholesterol level in the blood. Whether saturated fat causes heart disease, there’s been several randomized controlled trials that have refuted that. So we can say for certain that the diet-heart hypothesis in that sense is not true. But whether saturated fat raises cholesterol levels is a more nuanced question to answer. So to deal with the easy portion of the question first, we can just go back to when this hypothesis, the diet-heart hypothesis first began, and that basically traces back to the 1950s. Ancel Keyes probably should be known as the premiere, sort of founder of the diet-heart hypothesis and as I’m sure most of your listeners know he had come out with his comparison between six countries, later expanded it into a study of seven countries. And he plotted the dietary fat intake of these six countries against their incidence of heart disease and he showed that there was this very clean straight line showing this linear relationship where the more fat people in a country ate the more heart disease they got. And of course there were a number of problems with this initial presentation, one of them was this is an ecological comparison which is the least reliable of any kind of observation because heart disease occurs in individuals and food intake data for a country occurs in a country. Populations don’t get heart disease, governments don’t get them, people get them. That’s the first problem. The second problem, as most of your listeners probably already know, there was data available for twenty two countries and when all those countries are included the line doesn’t look very clean at all, in fact you can draw the opposite line if you wanted to cherry pick six different countries. But in 1957, the state of the evidence was this… There were studies showing that if you fed people milkshakes where the fat was taken out of the milkshake and instead filled with corn oil or something like that, you would lower their cholesterol, and if you fed them milkshakes with butterfat or coconut oil or something in them, then you would raise cholesterol. And so some people such as Ancel Keyes were arguing a-ha here we have the evidence that people who are at risk for heart disease need to start decreasing their saturated fat intake so they can decrease their cholesterol.

Chris Kresser: Chris can I ask you a question, do you know how long those studies lasted?

Chris Masterjohn: They were in general a couple weeks. The majority of studies addressing this are based on the idea that plasma lipids reach their plateau from the effect of diet after about a couple weeks. There is different ways of trying to slice the data on exactly how long we should be looking at it and how we should look at the long term, and we can get to those in a couple minutes. But the American Heart Association just came back and said look, you have a statistical correlation here between cholesterol and heart disease you’re claiming, that doesn’t show that anything that changes cholesterol levels in gonna change heart disease rates. You need to do a clinical study and show that your treatment is affecting the disease outcome. In 1961, the American Heart Association took a totally different tune and it wasn’t because the state of the evidence changed, it was because Ancel Keyes and a few other people got onto that committee writing the report and a few other people left. So you had a political change and all of a sudden the report looked totally different it said now everyone should start decreasing their saturated fat and animal fat intake and increasing their vegetable oil intake if they’re at risk for heart disease.

So this is basically the beginning of the diet-heart hypothesis, and it hadn’t even  been tested yet in a clinical trial until several years after the American Heart Association started making these recommendations. What did those trials show when it was actually tested? The first one was published in 1965 and in this study, they fed people either corn oil or olive oil supplements and told each of these groups to reduce their intake of other fats, trim their meats more, reduce their butter intake and so on. So basically what you had was a replacement of traditional animal fats with olive oil and corn oil. And in this study the results were not statistically significant by the end of the trial but they were pretty close. And what they found was the corn oil treated group had the highest incidence of cardiovascular events and the olive oil was intermediate between the corn oil and the control group. The control group being the people who were eating their traditional animal fat. And these authors made a very sensible conclusion, which was that “under the circumstances of this trial, corn oil cannot be recommended as a treatment of ischemic heart disease. It is most unlikely to be beneficial and it is probably harmful.” So that’s a pretty good conclusion, right?

Chris Kresser: Makes sense to me.

Chris Masterjohn: Makes sense to me too. Now there is another group who published a trial, Woodhill and colleagues in 1978 and they had a different reasoning. They basically got the same result, the more vegetable oil diet had lower survival over the course of five years, the last trial was two years. And so you and I would probably say the same thing, maybe this high vegetable oil diet is possibly harmful and certainly not beneficial. But you wanna guess what they concluded? Here’s a quote, “It is concluded that men who have had myocardial infarction are not a good choice for testing the lipid-hypothesis.” So here it’s the study that’s the problem and not the hypothesis.

Chris Kresser: If the shoe doesn’t fit….

Chris Masterjohn: Right, so this is the paradigm that one beautiful hypothesis can prove an ugly fact wrong. That’s the way that they look at it. There were a couple other trials that were done that didn’t show any significant results, in one particular case they planned to do a ten year trial and they just did the trial for five years. They found that there were five deaths in the group eating corn and safflower oil and four deaths in the group eating peanut and coconut oil. Of course such a small number of deaths is not significant, it could be due to random chance. But at that point they decided that instead of continuing for the next five years and seeing what the difference between these two groups were, they were gonna pool these groups together and compare the combined group to the general population. So at ten years they never told us what the difference between the two groups was, and they just said that people who are in their study were healthier than people who weren’t. So they gave themselves credit for having a study that was good for you to be enrolled in.

Then the last two studies that looked at this were the two studies that were double blind, and in one case they only followed people for an average of a year, and the other case they followed people for eight years. Now in the case where they followed people for a year they found no difference between the group that was eating low vegetable oil and the group that was eating high vegetable oil. Not surprising since it’s such a short study. But the study that is the most interesting as a test of the diet-heart hypothesis, is the LA Veterans Administration Hospital Study. And this study was slightly over eight years long, and it was double blind. What they had were veterans who were in-patients in a hospital and they were randomized to eat every day, every meal for over eight years, in one of two different dining halls. And of course the people who were preparing the food, collecting the data, didn’t know which dining hall was serving which, neither did the people eating there. But in one dining hall they cooked the exact same food, day in day out, meal in meal out, but used a mix of vegetable oils, and in the other dining hall they cooked the exact same food but used butter. So here we have a great example of a long term study. Double blind, highly controlled, testing a single variable. Superficially, our first impression from the results is that there is support for the diet-heart hypothesis, because in fact the group that was fed vegetable oil had statistically significantly lower hard endpoint atherosclerotic deaths at the end of the trial. Now there are several catches to this, and several reasons why this trial, if you look a little more closely at it, suggests that vegetable oil is probably the last thing we wanna be eating long term. The first thing is that non-cardiovascular deaths were increased, statistically significantly. So that total survival was not different between the groups, and if anything may have been a little bit better in the butter group.

Chris Kresser: Ah the good old disease substitution.

Chris Masterjohn: Well that’s what it appears to be at first. It appears to be disease substitution. But there are several more catches. The first one is that the randomization was unsuccessful in making the proportion of smokers the same in each group. So that, the group consuming butter had 60% more moderate smokers and twice as many heavy smokers who were smoking more than two packs of cigarettes per day.

Chris Kresser: Not so good for your heart.

Chris Masterjohn: Right, smoking’s bad for your heart. So right away we’re not sure if it was the butter leading to the increased cardiovascular deaths or the smoking. But we can perhaps say that maybe butter is protecting against the effects of smoking on non-cardiovascular deaths. Now the other point was, if you looked at another paper they published about how they did this diet it appears that they took special precautions not to re-fry the vegetable oils because they considered them delicate. But it appears that they did not take this precaution with the butter. As a result, the amount of vitamin E in the butter was about 1/3, or even less actually, than you would expect it to be. So ordinarily you’d expect butter to have about 3/4mg of vitamin E for every gram of polyunsaturated fatty acid. And in this case, you had less than 1/5 of a mg. So you have less than a third of what you’d expect to be there. Now, good butter can range in fact, between .5 if it’s not grass fed to 1.3 if it’s grass fed on good grass. So basically what we have is a diet where they cooked the heck out of the butter, and maybe used really bad butter to begin with, and we’re feeding them a vitamin E deficient diet. Now what we see is maybe butter is protecting against the effect of vitamin E deficiency and smoking, on non-cardiovascular deaths and at best about cardiovascular deaths we can say we’re not really sure if it’s the butter, the smoking, or the vitamin E deficiency that increases risk.

Chris Kresser: And even recycled butter did it, cooked three times.

Chris Masterjohn: Right, now here’s the final catch that makes this study really scary. If you look at the survival curve for non-cardiovascular deaths, it looks roughly equal for the first seven years of the study. So this increase that you get begins occurring at seven years and non-cardiovascular survival starts basically falling off a cliff between years seven and eight, and continues falling off a cliff, in the last data points greater than eight years, that was really about three or four months. So in the last three or four months you get even greater fall in survival compared to what you had in the preceding year before that.

And you can imagine that survival would be abysmal if this study were carried on for nine or ten years if you look at this graph. So what these authors were scared about was, it’s possible that when you consume vegetable oils for seven, eight, or nine years, it’s only then that you start to see increases in cancer and other deaths. So what they suggested was in the future we have a very difficult question to address maybe when we do these trials, we consider anything less than five years completely inadequate and consider that these trials have to go at least eight years. But instead of making longer trials, they swept the issue under the rug. Stopped doing these types of trials, and that’s the last one of its kind. So what we’re left with is, the diet-heart hypothesis on the whole, completely fails to indite saturated fat in causing heart disease, and seems to hint that over the course of seven, eight, nine years, consuming vegetable oils increases the risk of cancer and may increase the risk of all kinds of adverse effects that we didn’t anticipate.

Chris Kresser: I’m sure Dean Ornish will be very upset to hear that.

Chris Masterjohn: I’m sure he will and I suggest he take a look at these studies.

Chris Kresser: Well you know this brings up a few points, number one, you can’t just read the abstract because obviously when you do that you’re depending on the author’s interpretation of the study which as we’ve seen is not reliable. And you’re missing all the juicy tidbits that you just elucidated for us, that you get by reading the full text.

Chris Masterjohn: Right, in this case you have to read figure 14 if you wanna see that the deaths were increasing after several years, so this was a really big paper you need to read the whole thing and look at all the graphs if you wanna make some sense out of it.

Chris Kresser: Right, so this is why we need folks like you and Stephan (Guyenet) and others put there doing that hard work. This is one of these things like, don’t try this at home type of thing. I wanna mention an article I’m not sure you saw back in January that Stephan published it’s called Does Dietary Fat Increase Blood Cholesterol, An Informal Review of Observational Studies. Basically what he argued in that article by reviewing the studies was that yes, dietary saturated fat does increase cholesterol in the blood, but only in short term. And that if you look at longer term studies there isn’t really a significant effect. What do you think about that?

Chris Masterjohn: Well first I just wanna say that I love Stephan’s blog and out of all of the research-science based blogs that I read Stephan’s is definitely my favorite. I did read that blog post, and I agree up to a certain extent, I think it’s slightly more nuanced than that. In the epidemiological studies, I should say just to begin with, we have this sort of conundrum, it’s kind of a philosophical conundrum when we’re looking at what types of studies do we look at and how do we interpret them. I like to compare this to the uncertainty principle in chemistry or physics where if you try to look at an electron’s location you don’t really know anything about its velocity, and if you try to look at its velocity you don’t know anything about its location. I might be screwing that up a little but, maybe it’s momentum. In any case we have a similar thing when we’re trying to look at observational studies and trials. In observational studies you have a real world context, but you have no idea what the cause and effect pattern is. You can’t attribute anything to, an effect to a specific cause, when you’re just looking at statistical correlations and observational data. On the other hand, you can be absolutely certain that your results apply to the real world because you’re looking at them in the real world.   On the other hand if you’re looking at randomized controlled trials, you get to the point where you can come very close to certainty about cause and effect but then you have no idea that translates outside of the laboratory into the real world situation. So what we need to always do is try to splice the data as many ways as we can, and try to fit the data together and look at the big picture. And I think what Stephan did is a really important step in doing that. So what we can see from these epidemiological studies is, a high saturated fat diet does not seem to be associated with increased cholesterol levels. One of the differences is that we’re looking at people eating these long term. But the other difference is that if you look at a high saturated fat diet, you have a mix of whole foods that have tons of other things in them. So you can be eating more saturated fat cause you’re eating more meat, you can be eating more saturated fat cause you’re eating more coconut, you can be eating more saturated fat cause you’re eating more, some kind of cake, junk food from Starbucks that has saturated fat in it. There’s lots of different foods that have saturated fat in there, and the things that they are associated with such as the vitamins and minerals and proteins in meat, or the specific types of fatty acids in coconut, or the junk food in some of these junk food products may have very different effects on cholesterol. In the randomized controlled trials what we’re usually seeing is the effect of a specific fatty acid or a specific fat, ya know take those milkshake studies. They took the fat out of the milkshake and they put the corn oil in. So you’re seeing the effect of the fat but the food is staying the same. So, I think what Stephan’s post is showing is that over the long term, diets of whole foods rich in saturated fatty acids, together with whatever other confounding variables that we might not be able to identify, don’t seem to have an association with cholesterol levels. But if we look at this trial that I was just talking about, the LA Veterans Administration Hospital Study, we see something a little bit different. What we see is over the course of eight years, there is still an effect of cholesterol when the only thing that they were changing was the fat in the diet. These people weren’t eating more or less meat or protein, they were only eating butter versus vegetable oils. And the saturated fat group did have higher cholesterol levels, I will say one caveat which is that there’s a hint that maybe at the end of the study when we start to see these differences in non-cardiovascular survival, we might be seeing a leveling off of the difference between the two groups. So what I’ll say now is I think that saturated fat, by itself, isolated from the rest of the dietary context, probably does increase cholesterol levels, but there is, I’ll leave it as an open question that it’s possible that it’s not the case over the very long term.

Chris Kresser: Okay well that’s a perfect segue into the next phase of this which is, okay let’s say saturated fat does raise cholesterol levels in the blood, or let’s say we have high cholesterol levels in the blood for some other reason. This lipid hypothesis that high lipid levels in the blood cause heart disease, let’s get into this.

Chris Masterjohn: Alright so the lipid hypothesis in terms of its name, dates back to around the 1970s or so. And Daniel Steinberg who was the head of the Coronary Primary Prevention trial and the NIH concensus conference that Time magazine was siting when it came out  with that article with the frowny bacon face. He was probably the first person to use it in print, but it was probably it seems to be Pete Ahrens a couple of years later who was the first person to popularize the term lipid hypothesis. What they both meant was the same thing, that increasing cholesterol levels in the blood or decreasing them could alter the risk of heart disease. Now Pete Ahrens, if you read the article that he originally wrote, he seemed like a very open minded scientist who was hopeful about the lipid hypothesis but wanted to see it tested. But you’ll often see sited as a cholesterol skeptic, because he remained very skeptical about this connection between saturated fat in the diet and heart disease risk. And if you read his original article you can see why. He said look we’re testing the lipid hypothesis, but we need to test it in different populations, and we need to test it in different ways. So we can test it with a drug, but if the drug is effective it doesn’t mean that food will be, or vice versa if food is effective that doesn’t mean the drug will be. So we need to, he was basically saying what I was just saying, we always need to slice the data in as many ways as we can, look at it from as many angles as we can. But historically the origin of the lipid hypothesis traces back to the cholesterol fed rabbit, and this goes back to the days of Nikolai  around the turn of the 20th century in 1913. And Anitschkov’s cholesterol fed rabbit is often dismissed by what we can call cholesterol skeptics as irrelevant to humans because it’s a rabbit. And I think this is another case of mistaking diet heart hypothesis for lipid hypothesis. If you read Anitschkov’s work he never, ever, ever, said that his feeding cholesterol to rabbits and producing heart disease indicated in any way that feeding humans cholesterol would cause cholesterol in humans. Anitschkov was looking at a metabolic model of hypercholesterolemia. And what Anitschkov found was that if you increase the level of cholesterol in the blood of the rabbit, in this case by feeding dietary cholesterol, you could induce atherosclerosis in the rabbit. Now it’s true that the rabbit is probably not the best model for human disease, but the cholesterol fed rabbit model is incredibly useful for several reasons. And one is that so many other hypotheses had been tested in the rabbit leading up to Anitschkov’s experiment and they all failed miserably. So in these experiments they injected rabbits with bacteria, all kinds of bacterial toxins, heavy metals, chemical toxins, plant toxins, hormones, they increased blood pressure by hanging the rabbits upside down by their feet, restricting the aortas, they gave physical injuries to the arteries by cauterizing them with steel wire, by damaging them with silver nitrate, all kinds of things that they did to these rabbits. And some of these treatments, many of them in fact, did induce some arterial injury. But none of them induced anything that looked like human atherosclerosis. When Anitschkov fed cholesterol to the rabbits, what he produced was something that looked very much like human atherosclerosis. Yes there are differences that you can point out in the model, but this was the first and only thing in rabbits that produced something that looked like human atherosclerosis. Now, one of the reasons that we can increase our confidence that this is a valuable model is because subsequently it was shown that if you could induce hypercholesterolemia in animals, now I’m calling it hypercholesterolemia just for now because this is what Anitschkov thought he was inducing, this is what most people who are researching this think they’re inducing, we’ll get to the nuances later. If you can induce hypercholesterolemia in the baboon, you can induce atherosclerosis. In fact you can do it in a cat, you can do it in a chicken, you can do it in a chimpanzee, a dog, a goat, a guinea pig, a hamster, a monkey, a mouse, a parrot, a pig, a rabbit, a pigeon, a rat. You can do this in any of these animal models not necessarily by feeding cholesterol, but as long as you find some way to induce hypercholesterolemia you can induce atherosclerosis in these animal models. Now the generalized ability to all these different animals regardless of their metabolic type, their dietary type, seems to suggest that there is something in this model that’s generalizable to humans.

Now one of the reasons why we should pay close attention to the rabbit though, I’ll admit right off the bat if you wanna test a hypothesis like this in an animal it should probably be a guinea pig because guinea pigs have the closest similarity to human lipoprotein metabolism and vitamin C metabolism and some other things. But the reason the rabbit is useful is because so many things were tested in the rabbit that Anitschkov was able to develop a very complex concept of the multi-factorial nature of heart disease just based on research in the rabbit back prior to 1930 or so. And this is what he said, he said that if you wanna induce atherosclerosis you need to have hypercholesterolemia, but there are many other factors that will alter how bad the atherosclerosis is and exactly how it progresses, besides hypercholesterolemia. So he said for example that blood pressure would aggravate it. Inflammation he said would aggravate it. Infection and toxins he said would aggravate it. Thyroid hormone he said would protect against it. Sex hormones would protect against it. Iodine would protect against it. All these different factors, and there are more if you read what Anitschkov wrote he had a very complex view of heart disease. And he identified all these that we still talk about now, even in the cholesterol skeptic field, Anitschkov was talking about them back in the 1920s and 30s because of the cholesterol fed rabbit model. So that’s the key thing where I think we really need to pay attention to this model.

Now here’s the other thing, Anitschkov actually proved the idea false, that cholesterol causes heart disease. Now you say woah wait a minute I thought we were just saying Anitschkov proved cholesterol does cause heart disease. Well in fact he proved something much more nuanced than that. So here is the deal, if he fed the rabbits cholesterol they would get atherosclerosis. But if he injected them with cholesterol they would not get atherosclerosis. So what’s the first thing that occurs in your mind if injecting cholesterol doesn’t have the effect?

Danny Roddy: Chris I’ll let you handle that one.

Chris Kresser: Must have something to do with the metabolism of cholesterol from food.

Chris Masterjohn: Yeah exactly there’s something about the metabolism and it’s not just about the cholesterol. So when you feed cholesterol it gets packaged into lipoproteins and they get secreted into your blood. If you inject cholesterol into the bloodstream there’s no lipoproteins, it’s just cholesterol. So it’s not the cholesterol in the blood that’s causing the heart disease Anitschkov proved this in the cholesterol fed rabbit model way back in the 1920s and 30s. So this is an amazing fact that the people who support the lipid hypothesis as it’s called, tend to ignore. Now if they took the blood from the cholesterol fed rabbit, isolated the lipoproteins and injected the lipoproteins into rabbits then the rabbits would get atherosclerosis. So this goes back to the distinction you wanted to make at the very beginning of our interview. We need to distinguish between cholesterol and lipoproteins.

Now what does a lipoprotein look like? Well I’m gonna simplify, it’s like a round ball, it’s carrying some fat, some cholesterol, and some nutrients, and it has a membrane that are made up of certain types of lipids called phospholipids that help it be transported n the water soluble environment of the blood. And those phospholipids are rich in all different kinds of fatty acids including polyunsaturated fatty acids. And of course there’s also an important set of proteins in the membrane that are responsible for directing that lipoprotein to go where it’s supposed to go. As it turns out from the molecular biology that we’ve developed over the course of the years, what happens in the lipoprotein particle in order to cause atherosclerosis is the polyunsaturated fatty acids in the membrane of the lipoprotein particle are oxidized, and this basically means molecular degeneration, the molecules are falling apart. And once they oxidize they become toxic and in order to protect the blood vessels from these toxic degenerated lipids, the immune system comes along and forms an atherosclerotic plaque. That’s basically a protective mechanism but over time if you get accumulation of these toxic lipids you get inflammation, other sources of oxidative stress, these plaques fall apart causes a clot and this is what ultimately leads to a clot in the blood and then a heart attack.

Chris Kresser: So Chris lemme just stop you and recap a little bit for those folks that might be getting a little bit lost. We’ve known for quite a long time that cholesterol plays a role in heart disease, that’s the infiltration theory that Anitschkov mentioned, but we also know that it’s not the sole player and there are several other factors that determine whether an elevated level of cholesterol in the blood will cause heart disease, and that’s the combination theory. And one of the things that determines that is whether the LDL particle, or more specifically the polyunsaturated fat in the membrane of the LDL particle oxidizes.

Chris Masterjohn: This is exactly right. Let’s break it down this way… Anitschkov thought what he was discovering was that atherosclerosis was not a disease of degeneration, it was a disease of infiltration. That meant it wasn’t that anything was going wrong and falling apart and breaking down, it was that there was too much cholesterol in the blood. However, the injection studies we talked about showed that it wasn’t too much cholesterol, it was in Anitschkov’s view too much lipoprotein. What Anitschkov got wrong was that he didn’t realize that it wasn’t the abundance of lipoproteins in the blood, but in fact it was the degeneration of the lipoproteins in the blood.

So when it comes down to it, what we wind up with if we wanna have a proper understanding of what happens, is that yes lipids are involved though we shouldn’t distinguish between a lipid hypothesis and a non-lipid hypothesis, lipids are involved. What we need to distinguish is between the infiltrating idea that it’s just too much lipid, and the degenerative idea that it’s about those lipids breaking down. So once we realize that it’s about the degeneration of these lipids, then we can start to understand what are the metabolic factors that effect the degeneration of lipids, and how do we move beyond our understanding of the amount of cholesterol in the blood to how do we protect these lipoproteins from degeneration.

Chris Kresser: Exactly and that’s what I wanna spend the rest of the show talking about and what’s gonna surprise a lot of people I think are the things that protect against that oxidative damage or that breakdown of the lipoproteins are in some cases exactly the opposite of what we’ve been told to do to prevent heart disease. The interesting thing about this, Chris and Danny, is you still often hear people say God, you eating all that bacon? You’re gonna clog your arteries. Which sounds like the infiltrative theory, you eat cholesterol, your arteries are like pipes and the cholesterol’s just gonna accumulate in there like junk in a pipe and then the blood won’t be able to move through it.

Chris Masterjohn: That’s exactly the problem with the conventional theory as we know it today and in fact that’s another beautiful thing about Anitschkov’s work, he showed way back in the day that arteries were nothing like pipes and in fact this was an inflammatory process and everything we understand about inflammation today Anitschkov showed in the cholesterol fed rabbit model way back in the day. Arteries are nothing like pipes you don’t have anything clogging anything up you have this active process of the immune system trying to protect the blood vessels. In any case the serious problem with the idea that eating saturated fat is gonna make your arteries clog up is regardless of what the long term effect of saturated fat is on cholesterol levels. Maybe it increases them, maybe it doesn’t, I think it probably does long term. Regardless of that, saturated fat can actually help protect against oxidative stress because saturated fats are not vulnerable to oxidative degeneration. It’s the polyunsaturated fats that are very delicate. They’re not bad, and they’re not toxic, but they’re very delicate. I like to think of them like glass. You use glass for a lot of things because it’s useful, like when you drink water you use a glass. But if all you had around your house was tons of glasses that you weren’t using and all kinds of things made out of glass and they were piling up on the counter and they were all over the floor, you’re probably at some point gonna break a lot of them just because you have an over abundance of really delicate things. That’s the thing with polyunsaturated fatty acids, when you have an over abundance of these very delicate fatty acids they are very vulnerable to oxidation, and that can actually promote oxidative stress. So what we really wanna understand about fats is that saturated and monounsaturated fat are the ones that are fairly stable and therefore they’re protective, and polyunsaturated fats are the risky ones because they’re so delicate.

Chris Kresser: Right which of course are the ones which were being promoted as heart healthy for so many years by the American Heart Association.

Chris Masterjohn: Exactly, when Time magazine came out in 1984 with that sad bacon and eggs face article they said basically that the American Heart Association is finally proved right, when it was telling people 23 years ago to get rid of the animal fat in their diet and start eating corn oil. Well it was that same year that it was shown that what’s causing atherosclerosis in the LDL particles was the oxidation of these delicate polyunsaturated fatty acids in the membrane so Time Magazine probably should have made a retraction and said hey wait a second, these vegetable oils might be making the LDL particle much more vulnerable to oxidative regeneration but they never made that retraction.

Chris Kresser: Oops. Sorry about that. Let’s talk about another risk for oxidized LDL which is the particle size of LDL. A lot of people are aware now at least in the paleo, primal, Weston A Price world that not all LDL is created equal, so to speak, and that you’ve got at the extremes two different types of LDL. You’ve got large, buoyant or sometimes called large, fluffy LDL and then you’ve got small, dense LDL and the small, dense LDL is more likely to become oxidized and that’s one of the reasons it’s problematic so can you tell us a little about that?

Chris Masterjohn: I’m gonna give you my take on this and I think in this case I’m probably gonna ruffle a few feathers here, and before that let me just give a very basic and simple primer on what I think are the main factors contributing to oxidation. We’re concerned about the oxidation of the LDL particle. There are basically three factors here, actually let’s say four. One is the basic vulnerability of the LDL particle and that’s how many delicate fatty acids does it have in it that are vulnerable to oxidation. The second thing is antioxidants. So when the liver sends this lipoprotein out into the blood it packages it with antioxidants that will protect against the LDL particle. The third things is oxidants, once the LDL particle is in the blood, or the VLDL particle and so on, these lipoproteins are facing oxidants in the blood that are produced from our metabolism, toxins, inflammation, and so on, and those oxidants will eventually deplete the antioxidants and then the oxidation ensues. But, what causes the final outcome of this interaction between antioxidants and oxidants to lead to atherosclerosis? Well that missing factor is  time, okay? Say you have some high vitamin cod liver oil in your refrigerator. You take it out every so often, you take your half teaspoon or whatever, and you put it back in. What would happen if you took out that high vitamin cod liver oil and left it on the counter with the cap open for three weeks?

Chris Kresser: Oxidative damage.

Chris Masterjohn: Right. And what’s the key factor there? It’s time. The time that it’s exposed to the oxidants. So we know from genetic studies and from metabolism that the amount of time that the LDL particle spends in the blood is a major determinant of atherosclerosis risk, and that the amount of time it spends in the blood is primarily dependent on LDL receptor activity because the LDL receptor is what takes the LDL particle into the cell, delivers those nutrients to where they wanna go. Okay, we know that people who have genetic defects in the LDL receptor have dramatically increased risk of heart disease. People with genetic defects that increase the activity of this receptor have dramatically reduced risks for heart disease. So you have all this evidence that the amount of time that the LDL particle hangs out in the blood is going to be a main determinant of heart disease risk.

Now it is in this context that I try to interpret, what do the markers that are associated with the risk of dying of heart disease mean. So two of those markers are the total to HDL cholesterol ratio, and the LDL particle size. What happens to these two markers when the LDL particle spends too long of a time in the blood because of poor LDL receptor activity. Well one of the things that happens is that LDL particle is exposed to a number of enzymes that take out the triglycerides, or fats, from the particles and take those fats up into the cell. What is this do to the LDL particle?

Chris Kresser: I’d imagine it makes it smaller.

Chris Masterjohn: It makes it smaller, and it makes it denser because cholesterol is smaller and denser than triglycerides. So if you take out the triglycerides and leave the cholesterol behind, the LDL particle gets smaller and denser. Okay, the second thing that happens is, as we already talked about, the LDL particle starts to oxidize. When the polyunsaturated fatty acids in the LDL membrane oxidize, they get cleaved off from the membrane and they get transferred onto lipoprotein A, or Lp(a). And when that happens the LDL particle gets smaller and denser. Now what’s the other thing that happens, the other thing that happens is LDL and HDL interact with one another so that triglycerides are transferred from LDL to HDL, and cholesterol is transferred from HDL to LDL. This makes the LDL smaller and denser. What else does it do? It increases the amount of cholesterol in the LDL particle, and it decreases the amount of cholesterol in the HDL particle. So as far as I’m concerned, all of these markers such as the total:HDL cholesterol ratio or the LDL particle size, can simply be seen as markers for poor LDL receptor activity, and the LDL particle spending too long of a time in the blood. But they are not in my view the cause of atherosclerosis, it’s the oxidative degeneration that also takes place when LDL receptor activity is poor and the LDL particle spends too long of a time in the blood. So I think it’s a great mistake to try to say whatever changes the total:HDL cholesterol ratio into a more favorable ratio is a good thing. And I think it’s likewise a mistake to say whatever changes LDL particle size to make it larger and fluffier, is a good thing. Now, this does not exclude the possibility that the total:HDL cholesterol ratio or the lipoprotein particle size play a causal role in atherosclerosis, there are theories for both of these. For example in the case of the ratio, people say oh it’s about reverse cholesterol transport, you want the HDL to carry the cholesterol out of the plaques and back to the liver. My problem with this type of reasoning is, the one test of this hypothesis in humans was with the cholesterylester transfer protein inhibitor CETP inhibitor Torcetrapib, and it killed people left and right. That is what is known in the research world as an epic fail. There’s an old aphorism that can describe that trial which is the experiment was a success but the patient died. Because it was a success, the drug expectedly increases the amount of cholesterol in HDL and expectedly decreases the amount of cholesterol in LDL. It was a success, but the patient died. Now my question is, why should we apply the exact same logic to LDL particle size and assume that everything that affects LDL particle size in a so called favorable fashion is going to have a positive outcome, I don’t think we should. Nevertheless, there’s a hypothesis that small, dense LDL is more likely to fit through the endothelium, to get through the lining of the blood vessel and get into the area where you’d produce atherosclerotic plaque and it’s also more easy to oxidize. I’m very skeptical about this oxidation thing simply because when you take out small, dense LDL from someone’s blood, the evidence shows that it already is partially oxidized. Well gee why would that be? Because when LDL spends too long of a time in the blood it oxidizes and gets small and dense. So I don’t see any good reason to move beyond trying to increase LDL receptor activity and protect LDL from oxidation.

I will say this, just to get it out there for fairness’ sake. Eating cholesterol improves LDL particle size, and decreasing carbohydrate intake improves LDL particle size. And this is because apparently when VLDL is secreted with more cholesterol and less triglycerides, it’s ultimately metabolized to large, fluffy pattern A LDL instead of small, dense pattern B LDL. So eating cholesterol and reducing carbohydrates does improve that, I just don’t think it’s a good idea to make assumptions based on these surrogate markers for health outcomes.

Chris Kresser: Right, yeah so the name of the game, according to our current understanding, is to support healthy LDL receptor site function, lessen the amount of time that LDL is floating around the blood, and to reduce the chance that LDL will oxidize which is related to that first goal. So you mentioned in one of your articles, there are no specific anti-oxidants we can take to specifically prevent that. So two questions, and the second question will kind of lead us in to the next topic that I wanna talk about. Is there a way for people to improve their LDL receptor function and what are some of the main things outside of diet and what we’ve been talking about so far that regulate LDL receptor site function.

Chris Masterjohn: Okay, so here’s the basic big picture. The LDL receptor is expressed on many cells and plays a role in taking up LDL particles in many tissues. This includes the adrenals and the sex organs to produce the adrenal steroid hormones and sex hormones. So LDL receptor activity is a good thing. But quantitatively, meaning the shear amount of cholesterol that’s converting into bile acids is much greater than the amount of cholesterol that’s converted into these other hormones. Consequently the liver, which is responsible for making those bile acids, is the main site where the LDL receptor is expressed. This is how the liver contributes to blood cholesterol levels. It’s not by the amount of cholesterol it makes, all your cells are making cholesterol the liver mostly makes cholesterol for itself, not for the whole body for the most part. But the main way the liver regulates blood cholesterol levels is by expressing the LDL receptor making bile acids, and excreting those bile acids into the intestines. Now pretend you’re a liver cell and think to yourself, how much LDL receptor am I gonna make, how much LDL am I gonna take into the blood at any given moment. You’re two concerns are basically how much cholesterol you have on hand, it’s kind like managing your finances you wanna have a stable amount of money for your basic expenses before you determine how much you save or how much you spend. So it’s concerned for itself that it has its basic needs met for cholesterol, and then it’s concerned for the rest of the body. And this is true also of the sex organs and the adrenal glands too. The LDL receptor is going to respond to the needs of the body as well as the needs of that cell. Now the needs of the body are primarily communicated by thyroid hormone. And above thyroid hormone we seem to have leptin. So basically what’s going on is leptin is communicating the master governing signal about whether we are in a state of abundance or not. What are you gonna do when you have plenty of nutritious and satisfying, calorically dense food available? Well you’re gonna eat until you’re stuffed, you’re gonna do what you and your wife have been doing and make some babies. So leptin is basically communicating to the body that it’s time to get your groove on, to do what humans are biologically designed to do, to reproduce. It’s the signal that we’re in abundance, it’s time for virility and for fertility. Now, in this scenario leptin is kind of like the chief executive office, I know there’s things that control leptin, but in terms of communicating this abundance signal leptin is like the CEO of a company or the commander in chief of the armed forces. Thyroid hormone is like a general, so thyroid hormone is under the hierarchy of leptin but it’s the main signal that’s communicating this fact that times are abundant, it’s time to ramp up our energy, our virility, our fertility, time to reproduce and do all of these great things.

Now, you can see this pattern of communication if you just look at the LDL receptor gene. It has two regulatory elements in it, two pieces of DNA that are made not for producing a receptor but for communicating the needs of the cell and the body. One of those is to communicate the levels of cholesterol in the cell, the other is bound by thyroid hormone and its receptor. So you can see right there, when the cell needs more cholesterol or when the body is telling the liver and telling the sex cells and telling the adrenal cells that life is abundant, things are abundant, this is when we get LDL receptor  activity ramped up. So what does this say about the primary problems of LDL receptor activity in our society? Well it’s not genetics, you can have genetic defects in this that’s where you get familial hypercholesterolemia. But we know that we have an epidemic of leptin resistance because it appears that obesity is very intimately tied to leptin resistance, and we can presume that this leptin resistance is basically a failure of the body to communicate the signal that there is abundance. So what we have is this epidemic where we have abundance but that signal is not getting where it needs to go there’s miscommunication in the body. I think that’s a major role in LDL receptor activity.

Chris Kresser: Right, yeah this sheds a really different way of looking at this whole high cholesterol  problem, leptin resistance or problems with leptin signaling and thyroid issues are probably one of the last things that people think about and some people don’t think about them at all including a lot of health care practitioners. So speaking of the LDL receptor, let’s talk a little bit about familial hypercholesterolemia cause you wrote a great article about that a while back that I think is a really useful way of looking at some of these problems. I think we have a question from a reader, Danny, maybe we could use that as a springboard to talk about it.

Danny Roddy: Yeah definitely. This one’s from hooray for butter which is a fantastic handle, what are Chris Masterjohn’s thoughts on living and thriving with familial hypercholesterolemia? Is there an alternative treatment besides statins? Is treatment necessary if you maintain a strict diet, fitness, and reduce stress? Is the VLDL number, and percentages more important? I currently have a 415 LDL, 85 HDL, feel great and getting stronger every month. I’m in my late 40s, my VAP tests show a very low count on VLDL with 95% large and fluffy LDL. As per our conversation over the past couple of months there doesn’t seem to be any easy answers, thank you. What do you guys think?

Chris Masterjohn: Alright, so first of all if this person’s name is hooray for butter I might be related to that person, we should probably be in touch we might be a third cousin or something. In any case, here’s the question so how do you deal with familial hypercholesterolemia, and I’ll be the first person to say that I don’t have the answer. I have some ideas and I’d love to share them but most of these ideas are things that need to be worked out in the field under supervision in order to keep an eye on the person’s health and ultimately what we need are studies on this because in the mainstream medical professional they’re still hung up on the idea that it’s the amount of cholesterol in the blood so all of the therapy is based on reducing it. And the therapy does seem to have some benefit especially in the extreme cases of people who have two copies of this defective gene they need to get liver transplants or in some cases they just take their blood out, take the LDL particles and put the blood back and this can extend their life somewhat. Of course what they’re doing is taking out all the oxidized LDL because the LDL are oxidizing.

So here’s the deal, you can reduce a person’s expression of this clinical phenomenon in a couple ways, one is by giving them statins, I’ll tell you right now I’m not a big fan of statins but the statins will increase the LDL receptor activity in the liver by inducing a local cholesterol deficiency in the liver cell and that can have a positive benefit in this particular disease but it can also have some very nasty side effects as I’m sure you’re well aware. The other thing that really needs some attention, and I wanna emphasize that this needs very close supervision if it is to be experimented with, thyroid hormones will increase LDL receptor activity in someone with heterozygous familial hypercholesterolemia meaning someone with one copy of the defective gene. Regardless of whether they are hypothyroid or not, because they have one copy of the defective gene that means they have one copy of the good gene. And that good gene is responsive to thyroid hormone. Now there were some experiments back in the beginning of the 20th century where they showed that you could normalize someone’s cholesterol levels regardless of whether they were hyperthyroid, in fact the diagnosis back then was so imprecise because they weren’t able to measure thyroid hormone and antibodies and so on. They showed that you could give small doses of thyroid hormone titrating up from a very small dose beginning I think with a quarter gram and working up to a maximum of two grams of armour thyroid if I remember correctly. I’ll put the exact numbers on my blog at some point. You could give these very small doses and you could normalize cholesterol levels with no side effects. Then some overzealous people went off giving huge doses of thyroid hormone and killed some people and this was completely abandoned. The only hint of it coming back was in the lipid hypothesis era back in the 60s and 70s and in that time period they tried using a synthetic, fake form of thyroid hormone, not the one that you treat hypothyroidism but this isomer that was very different it lowered cholesterol but it didn’t have some of the other effects and that had negative effects too. One thing that we need some very cautious experimentation with at the clinical level, is people using very low doses of thyroid hormone to see if this is a safe and effective way to treat it.

Chris Kresser: What about the idea of using iodine to upregulate thyroid function instead of thyroid hormone?

Chris Masterjohn: Well that’s another thing you could do and in fact they did that back in the cholesterol fed rabbit they did that. They used iodine and it had the same effect as thyroid which was to prevent the atherosclerosis and there’s some anecdotal evidence for that like David Brownstein uses high dose iodine and he says that it’s greatly reduced the number of people he has to put on thyroid hormone. There are other people, as I know you know, who say iodine can have negative effects on the thyroid so again this is something that needs close, supervised study. I don’t wanna tell people to go out by themselves and get thyroid hormone from Mexico under the counter or 100mg  of iodine and start eating bottles of it I do not want to advocate that.

Chris Kresser: Yes, please don’t. I just wanna throw in one more thing Chris, for people who are listening to this, regarding iodine and its relationship to autoimmune thyroid disease and its potential for causing flare ups there’s a great series going on at Paul Jaminet’s blog right now Perfecthealthdiet.com by a guy named Mario. He’s arguing that iodine only provokes a flare up or damages the thyroid in the absence of sufficient selenium. He’s written a couple articles about it there’s some interesting there to link to so if anyone’s interested they should head over there and check that out.

Chris Masterjohn: Yeah that’s a pretty logical thing and in general I think that’s true with a lot of different nutrients. They’re harmful when you take one but when you reinforce the diet adequately with a whole balance of factors can promote health.

Chris Kresser: Right, I just wanted to mention that because I know that no matter how many times we say don’t do this at home, for sure people are gonna try to do it at home. So if there gonna do it at least do it right.

Chris Masterjohn: Yeah exactly. But here’s the thing, here is what I think people can do at home. You have a great point that you should focus on your weakest link, but you can make a counterpoint to that in certain cases like this one where your weakest link is the thing that you can do the least about. There’s no totally safe, totally effective way to normalize LDL receptor activity in these folks. So what we can do is try to improve the things that we can most impact, and that’s the oxidation of the LDL particle to some degree, but to an even larger degree it’s preventing the inflammation and pro-clotting environment that comes downstream from the formation of the atherosclerotic legion. Anitschkov’s rabbits didn’t get heart attacks, why not? Because these plaques were stable, they never fell apart, caused clots they blocked coronary arteries. You see this across most animal models and one of the main factors might be that these animals, most of them can synthesize their own vitamin C and that not only prevents LDL oxidation but it stimulates collagen synthesis and it allows for the stability of these plaques. So here’s the thing, low LDL receptor activity is going to promote LDL oxidation no matter how little polyunsaturated fat you eat or how many antioxidants you take in. However, although it will contribute to inflammation to some degree, there are so many other factors that contribute to inflammation that it is not the specific cause of inflammation. So in these people, I suggest first priority should be optimize the inflammation, optimize the clotting cascade, you wanna look at all the clotting factors and the inflammatory markers and you wanna solve that piece of the puzzle. That’s what you can impact the most. What you can impact the next most, is providing adequate antioxidants in the diet and avoiding the stimulation of oxidative stress.

When I say antioxidants I do not mean something specific like blueberries. I mean the wide spectrum of antioxidants that are found in fresh, whole animal and plant foods. Co-enzyme Q-10 is important in the LDL particle you get this from beef and buffalo heart is probably the best source, and to a lesser extent in red meats, other meats and on down the line in plant foods. Liver is a great source of B vitamins and lipoic acid and all sorts of things that contribute to good energy metabolism which prevent oxidative stress. Plants, fruits and vegetables are good sources of polyphenols which through hormesis protect against oxidative stress. Raw fruits and vegetables especially are good sources of vitamin C, which although the LDL particle is, the fats in it are fat soluble, the blood is mostly water and in order to minimize oxidation of LDL in the blood you need vitamin C and all the water soluble antioxidants. You need to minimize inflammation because inflammation is a source of oxidative stress, you need to normalize energy metabolism, because taking in more energy than you can handle is a source of oxidative stress. By this I don’t mean caloric restriction, I mean normalize your calorie intake to what’s normal but increase energy capacity. Get the B vitamins, the co-enzyme Q10, all these different co-factors that you need for energy metabolism. In other words, eat a nutrient dense lacking refined foods, lacking vegetable oils, full of whole foods from both animal and plant products including animal organs. That’s the next thing you can do, and then after that, try to mess with cholesterol levels because cholesterol levels and LDL time in the plasma, those are the things you can affect least with familial hypercholesterolemia.

Chris Kresser: Right, it’s  shame we don’t have more data on people doing these things with familial hypercholesterolemia because I suspect there are a very small number ultimately that are following these guidelines that have it, it would be very interesting to see what the outcome would be over a period of time.

Chris Masterjohn: Right that’s the thing, and I just wanna really emphasize this anyone who has familial hypercholesterolemia should in my opinion be under medical supervision and if you go to conventional medical supervision you know what they’re gonna do they’re gonna give you a statin and so on and so forth. I will not tell people that they should therefore not be under medical supervision. If you don’t wanna take a statin, I don’t like statins at all, if you don’t wanna take a statin you need to find someone who is going to work with you, monitor all your clinical values, and optimize them in a supervised way. Familial hypercholesterolemia is not something to play around with. It’s not a ticket to inevitable early death, but if you don’t treat it, it almost is.

Chris Kresser: Yeah. Don’t self treat on this one folks. Well Chris thank you so much we’re getting to the end of our time here and I know there’s some questions that we didn’t get a chance to get to but it just means we’re gonna have to get you back on the show for part II. I think we can look at this as sort of the basics and the primer and the advanced course all put together, and then when we have you back the questions are gonna make a lot more sense because we won’t have to do so much of the background explanation we can just get more into answering the questions specifically.

Chris Masterjohn: Yeah definitely I’d love to be back Chris thank you so much.

Chris Kresser: Great, thanks again. We’ll hopefully talk to you soon Chris.

Chris Masterjohn: Alright great.

Danny Roddy: That’s gonna bring us to the end of this week’s episode. You can find all of Chris’ work at thehealthyskeptic.org. You can find me at Dannyroddy.com. Keep sending us your questions at thehealthyskeptic.org using the podcast submission link. If you enjoy listening to this podcast head over to i-tunes and leave us a review. Thank you for listening and thank you for your support.

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  1. Wes says

    Great information! Just a comment about the background noise though, the paper rustling or stuff happening while Masterjohn talked was really distracting.

  2. Nikki says

    Chris, this has been one of your best podcasts to date. I learned so much! I think the information about the oxidation process and how harmful that is in terms of cholesterol and heart disease was especially eye opening. Masterjohn is incredibly gifted at taking these complex processes and making them more digestible for us non-Phds. Thanks for having him on your show!

  3. says

    Just joined your website. I’m a practicing naturopath in Australia, ever struggling against the tide of mainstream, whilst preferring to swim together and be much more integrative. Really enjoyed this podcast. So good to hear voices sharing the info rather than just reading literature. Let’s me multitask. Thank you :)

  4. Steve says

    That was an exceptional interview; i learned a lot from it. If i am to understand Chrs M’s viewpoint, you would conclude that the mix of LDL particles between small and large is not as important as the total amount of LDL particles that carry cholesterol. IF this is correct, then a number of people in the Paleo community may be fooling themselves in to thinking that all is ok when most of their LDL particles are large. It may depend upon how many there are and for those on the high fat diet that might be as many as 2,000 particles floating around and potentially overwhelm the LDL receptors, hang around to long and degrade, get oxidized and cause an inflammatory reaction. Not so good. I guess the question may be what is a good marker- LDL particle number? What are your thoughts?
    Thanks for the outstanding podcast!

    • Chris Kresser says

      Maybe Chris M. can chime in, but I’m not sure that’s entirely accurate. From my reading of the research small, dense LDL are more likely to oxidize, and we can’t assume that everyone with high numbers of LDL has ox-LDL. The likelihood rises, but there’s not necessarily a relationship. That would depend on LDL receptor function and overall presence of oxidative factors in their diet and lifestyle.

      • gregory barton says

        I think what CM was saying is that time is of the essence: the longer the LDL particles are in the blood, the more likely the large particles will degenerate into small particles and oxidize. (Something about losing triglycerides – I couldn’t quite hear.) If the LDL receptors are blocked (whether through familial hypercholesterolemia or rT3) and the liver keeps on producing cholesterol then the numbers will rise. Thus high LDL numbers will correlate with cholesterol spending more time in the blood and more opportunity to oxidize. Correct me if I’m wrong.

        • says

          I’ll write a blog post about LDL particle size, but here’s the gist.

          First, LDL particle size can very easily be seen as a marker for time spent in the blood (because this leads to loss of triglycerides to cells and to HDL, and acquisition of cholesterol from HDL, more oxidation and other modifications, all of which make LDL small and dense). Since excess time spent in the blood is primarily a function of poor LDL receptor activity, and since poor LDL receptor activity is by far and away the most definitively established causal risk factor for heart disease, it makes sense to first and foremost consider small dense LDL as a risk factor because it is a marker for poor LDL receptor activity and long time spent in the blood. Thus, there is no reason to assume that treatments that boost LDL particle size through any means other than promoting better LDL receptor activity or preventing oxidation will actually prevent heart disease.

          Second, evidence to date suggests that LDL particle size does not add any predictive value to established risk predictors like the total-to-HDL-C ratio. (This, like small dense LDL is, in my view, a marker for poor LDL receptor activity and not a causal risk factor itself.)

          Third, LDL particle size testing may not be reliable.

          I didn’t go into points 2 and 3 much in this interview, but I’ll blog about them and in the q&a interview I’ll do with Chris K we can talk about those points.

          I do not think particle *number* is the issue to look at. Particle number generally increases, in my view, because more particles are synthesized or fewer are cleared. What we want is to promote clearance, but not to stop synthesis, so we don’t want to obsess over particle number per se.

          Chris

          • gregory barton says

            Thanks for the clarification. If I understand correctly, you are sayting that “number” is an unreliable marker because it could indicate either increasing synthesis or poor clearance and we cannot distinguish which is which. But in certain cases, would not one be more likely than the other? For example, if cholesterol goes up on a very low carb diet, would it not be fair to presume that the clearance is impeded, rather than synthesis is increasing. You alluded to this issue in a comment to the article Why is My Cholesterol So High on This Diet:

            “One thing to look out for is that extended low-carbing can decrease thyroid function, which will cause a *bad* increase in LDL-C, and be bad in itself. So be careful not to go to extremes, or if you do, to monitor thyroid function carefully.”

            I look forward to your article on particle size. However, if clearance and promoting receptor activity are the goal of arterial health, I’m sure many of us would welcome an elaboration on this subject too. For example, could you comment on Paul Jaminet’s claim:

            “Copper deficiency is, I believe, the single most likely cause of elevated LDL on low-carb Paleo diets. The solution is to eat beef liver or supplement.”
            http://perfecthealthdiet.com/?p=2547

            Is Paul Jaminet saying that remedying a copper deficiency would promote receptor activity and clearance? What is the connection with thyroid? Does copper deficiency on low carb/paleo lead to decreased thyroid production which leads to decreased LDL receptor activity which leads to elevated LDL?

            • says

              Hi Gregory,

              I haven’t reviewed the primary literature on copper and cholesterol metabolism, but this is what the copper chapter of the tenth edition (2006) of Modern Nutrition in Health and Disease has to say:

              “Blood cholesterol increases in animals fed copper-deficient diets, but results of studies on the effects of low-copper diets on human blood cholesterol are not consistent. Levels increased in some and declined in others, and copper supplementation increased low-density lipoprotein in a study in men.”

              Copper is also pretty widely distributed, though I agree copper status will be better if you eat liver. Overall, I think he has a point, but it should be considered very speculative. I think it is a stretch to conclude that this accounts for most cases of high LDL-C on low-carb diets.

              I agree that decrease in thyroid function on low-carb is a possible explanation for increased particle number, although so is increased clearance of VLDL from the liver due to choline or increased cholesterol output due to a lower PUFA-to-SFA ratio. Thus, one should consider the other markers, in particular the total-to-HDL-C ratio. If this is very high in addition to particle number but particle size looks good, the particle size wouldn’t comfort me, especially since low-carb may increase particle size through means that have nothing to do with increases LDL receptor activity and decreasing time spent in plasma. I would look at thyroid function, but the available tests are incomplete. For example, it is very possible that elevated free fatty acids decrease thyroid hormone receptor binding at the nuclear level. So I think you need to be very sophisticated in your approach to evaluating thyroid status.

              Chris

              • gregory barton says

                Thanks Chris. Your comments suggest that the issue is a can of worms for the layman – with the exception of TC to HDL ratio, which you stress over particle size. That’s a very interesting twist on the standard low-carb thesis: large and fluffy is benign.
                Further elaboration, at some future date, would be welcome.

          • Eric Lepine says

            That’s awesome Chris. Thanks for clarifying. I was also wondering the same thing…

            Great to have you two together on one show. Now, Chris needs to get Kurt Harris, Mat Lalonde, Stephan and you together for 2+-hour marathon!!! That would be the BOMB!!!!

            Cheers,
            Éric

          • Chris Kresser says

            Thanks for responding on this, Chris. You say: there is no reason to assume that treatments that boost LDL particle size through any means other than promoting better LDL receptor activity or preventing oxidation will actually prevent heart disease. I see your point, but the “treatments” that I would suggest to increase particle size also happen to be things that prevent oxidation (like reducing intake of PUFA, eating more SFA & MCT, exercising, etc.), so it would seem those treatments would reduce the risk of CVD (though not by altering particle size necessarily). Of course improving thyroid function would have a similar effect, if that were an underlying cause of poor LDL receptor function. I’m looking forward to part 2. I’ve reviewed quite a bit of evidence lately casting doubt on the accuracy of the particle size tests.

            • says

              Chris, I agree that those are things that should reduce CVD risk. I meant the comment targeted at treatments designed specifically to alter LDL particle size. By the way, I do think it is plausible that small dense LDL is in fact more atherogenic because it is smaller, but I think it’s just a hypothesis at this point, so I’m not ruling it out or ruling it in. The stuff you sent me was my first introduction to the technical problems with particle size assays, so thank you.

              Chris

  5. steve says

    Chirs: What you say is correct, but i am unsure/ unclear that just because you have lots of large LDL paticles and only a small amount of small LDL particles that it is clear sailing. In numbers, let’s say that you have Large LDL particle count of 2500 and small of only 150. Does this mean you have little chance of suffering with Oxidation risk no matter how pristine the diet via minimization of Omega 6, eating sat fats, and low starch and no sugar? If you look at the NMR report they would categorize this level of LDL particles as being dangerous, or very high risk. Granted the population selected is one that has been on the SAD diet, but the question remains.

    Thanks again for the very informative podcast!

  6. says

    Amazing podcast! I had trouble sleeping last night since the ideas were so interesting I couldn’t stop thinking about it, especially the idea that leptin resistance could be responsible for down-regulating the hepatic LDL receptor.

  7. michele bird says

    Thank you for the informative lecture- my question is : with hypothyroidism and familial hypercholestrolomia and a dr. prescribing eltroxin and statins and not knowing how much my m.d . really knows, how safe is my health – when is the second lecture scheduled for please

    NOT LIKING STATINS – SOUNDS REALLY SCARY

    wishing us all the best of good health

  8. says

    Once again I’m thrilled to hear some really smart people get together and have frank, analytical discussions of scientific literature on a controversial and confusing topic in a way that’s easy enough for the public to comprehend. I appreciate that the level of the discussion is high enough that practitioners can get some take-aways that are descriptive of mechanisms but also elementary enough that we can use our common sense to glean some great take-aways.

    Thanks for doing this. Looking forward to more, as always.

  9. Chollie says

    The podcast was great, lots of great info. I want Chris M, if he has the time, to consider this ‘real world’ example:

    Person A has an LDL of 100 and a total cholesterol <200. He happens to be on a standard high-carb diet deficient in many micronutrients, among other things. Of course, his doctor would be very pleased with these levels but an NMR test shows that his LDL is predominantly Pattern B.

    Person B on the other hand has an LDL of 180 and total cholesterol of 280. His HDL and Trigs are good and he happens to be on a low-carb diet taking a lot of pains to see he gets all his micros from either food or supplementation. Of course, his doctor will be quick to prescribe a statin and completely ignore the fact that the NMR shows his LDL to be Pattern A.

    Does Person A have anything to worry about? More importantly, does Person B have anything to worry about?

    • says

      Chollie, they both may have something to worry about. The thing to remember is that *no* lipid tests have any diagnostic value. They have risk prediction value, and they have value as metabolic clues. This hypothetical doctor is trying to treat cholesterol levels as if they are a disease, but they are neither a disease nor diagnostic for a disease.

      In both cases, there should be further evaluation. What are person A’s triglycerides? What are person A’s fasting glucose and insulin? A diet high in carbs and low in cholesterol is likely to reduce LDL particle size directly, but this may not be a problem, perhaps, unless it is associated with insulin resistance. In any case, person A should obviously eat a more nutritious diet that does not contain micronutrient deficiencies.

      Person B should get free fatty acids, a full thyroid panel including reverse T3, and various markers of oxidative stress.

      Hepatic triglycerides wouldn’t be a bad idea in either of them, nor would adding any of person A’s tests to person B and vice versa. Also, total-to-HDL-C ratio rather than total and LDL-C separately should be used. The point though is that these are clues, not diagnostics.

      Chris

  10. Jack Goldmaker says

    I’m a bit confused again Chris M. From what I understand, arteries harden from calcification as calcium is used from the body to plug any exposed muscle tissue as the arterial walls get eroded from free radicals.

    You state that small dense LDL phospholipid layers will be attracted into what? I had thought that the role of LDL in the arteries was totally different than its usual role of delivery. Much like a truck on a milk run, it has to go back and forth on a highway before it does its work in its local area. However, once in the arteries, any calcification or ischemia would be kamikazed by the LDL to coat the calcification and prevent platelet damage in the high speed tube. How does the oxidized LDL cause the calcification?

    • says

      Calcification of the media occurs in diabetes, kidney disease, aging, and vitamin K deficiency. This is very bad for blood vessel function, statistically associated with CVD mortality, and is not a protective factor.

      Calcification of the intima occurs in very advanced atherosclerosis in association with cell death. It is almost certainly disadvantageous, but it is not a major cause of heart attacks, as most of these occur due to plaque rupture or erosion secondary to inflammation, and only a minority occur in response to calcified nodules or protrusion of the plaque into the lumen. Calcification does not drive atherosclerosis, it occurs very late, probably in response to the cell death that accompanies advanced oxidative and inflammatory scenarios. Oxidation of LDL causes the initiation of atherosclerosis long before any calcification occurs.

      Chris

  11. Jack Goldmaker says

    Chris M. I am still confused because I learned from Mary Enig’s book as well as Sally Fallon Morrell that what they were saying was that cholesterol deposition is the LAST process in the damaging of the arterial walls. The example was “You cannot blame the ambulance for showing up at an accident as the cause of the accident”. Hence Calcium deposition took place before LDL ever showed up.

    Allow me then to use my own example based upon your podcast in laymens terms. You are saying, basically, that LDL is like a Ziploc bag and it contains all kinds of stuff like fat soluble vitamins, triglycerides and varioius fluffy and unfluffy particles of cholesterol.

    Various things in the blood cause these bags to shrivel up. So, lets say for a moment the artery is a small creek and if one dumps crude oil into the river, it simply dissipates. However, if one puts the oil in a zipper bag, it catches along the side of banks of the river. Then the bags begin to shrivel up and get sticky and make tar on the sides of the creek. Then something comes along and covers the tar with powder such as calcium to contain the spill.

    This powder then crystallizes and turns hard making the river bank more like a rocky outcropping. Then if any shiny new zipper bags full of oil come down the river, they smash into the rocks and spill cholesterol on them to polish it and make it so that platelets don’t get damaged?

    This is what I thought plaque was, and that if a large surge came down river the ‘current’ which wears down the older LDL zipper bags, (sort of like shrivelling up a bag with a hot air gun) snaps off the rocky outcropping and then a clog occurs, damming the river somewhere downstream.

    But the current is, really, not the problem it is the pollution in the river that is destroying the LDL bags, and this is somehow causing the bags to want to head to the shoreline because they are all now shrivelled up? That eating cream makes them healthy and shiny again, that the shrivelled bags are now quite easy to catch on the shoreline versus the shiny new ones. That they purposely migrate to the shoreline and infuse with it? That this is the ‘bad particles’ in the phospholipid layer (ie the plastic in the bag decomposes) that drives the older LDLs into the riverbank?

    And this is where I get confused. For I understand that calcium, if removed by chelation, will be automatically replaced by the body as it will rob calcium from the bones to replace the clog, as it does to STENTS. and stents are not made up of biological materials. Yet they are always clogging up. Does this mean that there is some sort of electrolytic action going on because even stainless steel is attracting the phospholipid layers of the zipper bags (LDL)?

  12. says

    Hi Jack,

    I’m not responsible for other people’s views of heart disease regardless of how much respect I give them and how much they deserve.

    Oxidized LDL is not an ambulance. It’s a toxic factor that causes atherosclerosis. Ambulances and police cars aren’t very good analogies because they imply something is either perpetrator or victim. LDL is a victim here, but once victimized it perpetrates damage. A better analogy would be infectious disease. The person who gets sick is a victim, and though they make others sick, you don’t call them a criminal or a perpetrator. If anything is an ambulance here, it would be the monocyte that forms a plaque to protect the endothelial cell from the toxicity of all the oxidation products within the oxidized LDL particle. However, quarantine is a better analogy than ambulance.

    I disagree with your analogy because you cite calcification as a protective factor. Calcification, to my knowledge, does not play a protective role. The immune cell plays a protective role by securing the lipid oxidation products within an atherosclerotic plaque, which protects the cells that line the blood vessel from their toxic effects. However, the “protective” plaque looks like this: relatively poor in lipid, rich in collagen, covered by a stable fibrous cap, without protruding much into the lumen and without calcium deposits.

    I’ve never claimed that cholesterol accumulation in plaque is a protective factor. To the extent I’ve claimed anything about it, I’ve said it’s not all that relevant.

    I’m not sure what your “current” is supposed to be analogous to. Plaque rupture is caused by inflammation and perhaps diminished capacity to synthesize collagen because of micronutrient deficiencies.

    Your analogy, in my opinion, makes things more confusing rather than clarifying anything. LDL particles aren’t anything like ziplock bags at all. Shriveling isn’t very analogous to oxidation. The LDL particle is supposed to get to the shoreline to transfer its contents there. However, it is not supposed to have all its contents destroyed when it does so. The shoreline shouldn’t be analogous to a plaque.

    Try this: the LDL particle is a cargo ship. It is supposed to land at various docks to deliver over the goods. However, it is also supposed to protect the goods so that they are in good shape when the ship gets to the dock. However, there are often pirates at sea, and they may attack both the people at shore as well as the cargo ships. If they block entry to the dock, the ship cannot refuel or purchase more ammunition for defense. If the ship is thus left at sea, it runs out of ammunition and the pirates are then able to effectively sabotage it, ruin its goods, and purposefully plant explosives and release infectious diseases on the boat. Then, when it does get near shoreline, the folks at the dock catch illnesses and are caught in terrorist explosions. Thus, the immune system, like a navy and national guard, rescues the cargo ships that have been attacked (oxidized LDL), and quarantines them and any toxic factors released from them in something like a superfund site, where the surrounding community is protected as best as possible.

    I’m not entirely sure what you mean in your last paragraph, but calcification is not caused by calcium, so of course chelating it isn’t going to do anything. As I said before, calcification of the intima during atherosclerosis is a very late event of advanced plaques that is precipitated by the process of cell death. Calcification of the media is a harmful factor associated with CVD but with quite different causes, and vitamin K deficiency might be a major part of it. Technically, it’s not really part of the atherosclerotic process.

    Chris

  13. Jack Goldmaker says

    Perhaps I have not elaborated on my perception of the Lipoproteins and how they work in the body in laymans terms. I understand the concept of the delivery vehicle much like I understand that insulin is also a transporter of sugar. However, I failed to explain that in my perception of it, LDL is indeed a delivery of its contents when in the vascular system. However, it is my understanding that nature herself has more than one purpose at times for various body systems. It is a necessity to have multi tasking, so while I have neglected to mention that I understand all of what you are stating about the delivery mechanism as well as the other Lipids when it comes to transporting their contents to the cells, I have also come to the conclusion that when the LDL and perhaps other lipids are in the high speed arteries, they have a different function, that of being suicide bombers when it comes to particles of calcium and other garbage in the blood that have been trapped by the fibrin used to repair the exposed arterial muscle that is growing inwards signalling the artery to close down to prevent a high pressure leak into the body cavity.

    Sorry, I neglected to mention that to me, there are two different functions for LDL, one in a static mode such as when on delivery like your cargo ship analogy. But in a high speed highway it collides with any accidents covering up the damage to prevent platelets from being ripped to shreds in a high speed tube. This is why I mentioned ‘current’ because I am under the perception that when one cuts into an artery blood spews everywhere like in an old Kung Fu movie. To me, LDL simply cannot do anything but travel when inside an artery due to the speed of the blood. It is like white water rafting.

  14. Jack Goldmaker says

    Yeesh! I just read what I posted. It sounds quite confusing. Let me simplify this.

    I AM ONLY REFERRING TO EVENTS WITHIN THE ARTERIES.

    I am suggesting that due to the DUALITY of IDL, that if one applies a voltage to the outer shell of IDL it changes from looking like a coin to looking like a soap bubble. A biochemical voltage that is, to the phospholipid layer. That it makes sense that LDL does something like that as well. Depending on the CHARGE of the phospholipids (ie. the outer layer of the lipoprotein) it has a different function. I am postulating that the electrical charge of the LDL in the arteries is a different charge than when it is on delivery.

    • says

      Hi Jack,

      I think we’ll have to agree to disagree on the mechanisms of atherosclerosis. I do not think it has anything to do with patching up a leak, and I think calcifying an artery is a horrible way of repairing anything.

      LDL does some delivery in the artery too. I agree it has more than one function, and glomming some stuff up could theoretically be one function, as in the case of mopping up bacteria or endotoxin. But I don’t think patching up holes in arteries is one.

      Chris

  15. Garry says

    Excellent info! This podcast goes on the All-Time list for sure, and I look forward to Part 2 (and 3 and 4 if we’re lucky!).

    Chris M, can you clarify what can be done clinically to improve LDL receptor function (and thus avoid LDL oxidation etc.)?

  16. HPTNS says

    Chris,

    I think I understand your views re- CVD causation, in which inflammation plays a key role in impacting upon LDL receptor mobilization. Thus, serum lipid levels and composition are only markers for potential problems.

    I am less sure regarding your views about the role of infection in causing or combining with inflammation and lipids, to lead to CVD. Some cholesterol skeptics argue that the reason that vascular disease is localized at particular points in the heart (or elsewhere), for instance, is that it is the combination of infection, inflammation and lipids, that leads to eventual MIs at specific locations.

  17. says

    Hi HPTNS,

    I’m not sure what you’re referring to by my views on the role of infection, but the localization of plaques is clearly related to hemodynamic factors. In any species, to my knowledge, including humans and rabbits, plaques occur in areas of disturbed blood flow. Shear stress, caused by uninterrupted parallel blood flow, increases synthesis of nitric oxide which is a protective factor in the optimal range, and, probably more importantly, upregulates tight junction proteins which decrease the permeability of the vessel. It has been experimentally demonstrated for near 100 years that plaques occur where the blood vessels are most permeable, and that anything affecting the permeability causes a proportional affect in the degree of atherosclerosis. Inflammation, for example, causes a general increase in permeability and thus enhances atherosclerosis. Exercise should theoretically have the opposite effect, since it increases blood flow and thus shear stress.

    Chris

  18. Jack Goldmaker says

    Hi Chris M.

    I am not stating that calcification of the arteries is a repair process. It is a permanent fix. Once the artery is fully clogged, arteriogenesis takes place in the nearby areas as the body grows its own bypass by creating new micro vessels that cannot be seen by conventional X ray technology.

    Chest pain is necessary for these microvessels to grow as it triggers the immune response. One can run a sharp knife along one arm and it will hurt and bleed, while a butter knife on the other arm will do nothing, and there will be no immune response. Thus CVD is a silent killer unless one exercises regularly and tolerates chest pain. After the artery is clogged solid, the body rejects any chance for a bypass to be man made by constantly filling Stents and clogging up the new bypassed arteries. We all saw how Dick Cheney was always going in for ‘maintenance’ work on his heart. How Bill Clinton was up on stage after his bypass surgery as a poster boy for the Heart Association. However these two fellows had a team of 20 surgeons who had hedged their bets on doing more bypasses for the average American.

    It would be nice if some sort of natural artery cleaning took place such as lipolysis, although I would not think it would be healthy to clean out an artery be it by catheterization or stent or other means. I would welcome a method to do this but from experience in technology the story of “If it ain’t broke, don’t fix it” comes to mind with a fully plugged artery. I would not be happy if a fully plugged artery was being unplugged slowly leaving dangerous bits of plaque able to break off at any sign of a sudden increase in blood pressure.

    According to the late Dr. Howard Wayne of the San Diego Non Invasive heart center, the difficulties today with the concepts of bypass surgery were all due to the fact that NO imaging technology existed, nor does exist that can measure the amount of micro vessels that are grown by the immune system around a clogged artery naturally. This can only be done after autopsy under a microscope.

    Thus, LDL has no part in the repair process of a fully calcified artery as it has been abandoned permanently by the body and a detour has been made by the blood being detoured into the collateral arteries which then stretch open slowly with much pain. However this pain is necessary because it signals the immune system to begin the repair process and grow new microvessels.

    Pain is from the collaterals under new pressure to expand much like those sausage balloons the clown at the birthday party is trying to inflate so that he can twist it into a sausage dog.

    One cardiologist once told me “But it IS broken” and offered to ream me out for 15 minutes so that he could collect approx $30,000.00 for the treatment according to US charges. He threatened me that I I would die if he was not allowed to do this. I also noticed at the time that the Ontario (Canada) association of Cardiologists at that time were lobbying the government demanding that each cardiologist in the province be allowed to do a minimum of 260 catheterizations (angioplasties) a year so that they could have an American like lifestyle.

    One does not need a surgery license to do angioplasties and this became a great income source for Cardiologists. Dr Wayne however, thought to manage plugged arteries with medications only and was quite successful during his years in practice.

    He had found this ‘natural’ bypass, and just like transplant rejections thought that cleaning clogged arteries was a waste of time because they just grew back clogged even more than ever. So LDL does clog and calcium does clog them up for good. Fully repaired by being fully clogged.

    Much like a pipe in the basement full of lime, rather than reaming it out and having chunks fly out of the taps upstairs, he patched in a small network of tiny plastic pipes rather than a large copper bypass. He did this by DOING NOTHING but allowing the body the time to let the immune system stimulate new growth. Like the example with the butter knife, nothing happens because nothing is damaged. However if an arm is cut open by a knife, there is much pain and soon, fibrin arrives and the repair process begins.

    This is quite similar to the ‘Non oxidized LDL’ arriving at a site where there is damage is it not? I can only surmise that the possibility exists that there are outer voltages on the outside of the LDL that work like docking stations depending on their values when they arrive at the liver etc. Your theory of the outer layer of the lipids seems to align with this concept as well. Has anyone charted the values of the various sites of the body where these events take place on an electrical level? Potential differences etc?

    It appears that if Intermediate density Lipoprotein does this then why does it do this. Why does it go flat like a coin? Is it due to the fact that it is empty, this would mean that there would be sensors inside the lipoprotein indicating that it is empty. Suddenly it looks to me more like an email delivery system than a chemical one, where there is a link layer as you are describing, like chemicals, wheras there is also a transport layer that signals the various Lipoproteins with voltage values.

    No wonder this is not well known should the electronics industry get an hand on it.

  19. Peter says

    Chris,
    I’ve got an off-topic question. I heard you say once that you eat a 24-hour soured sourdough bread. I’ve googled for it but can’t find it. What’s it called? Thanks – Peter

  20. taylor says

    Hi Chris
    I know your busy so I will try and make this brief. I am 22 years old weigh 141 pounds and am just shy of 5 feet 8 inches. I am writing to you because I have gotten some troubling blood test results and have also have a few associated problems. To be brief, I have been having trouble putting on weight despite upping my calorie intake to about 4000 calories a day. My diet is paleo with a focus on whole natural foods with the exception that I do eat dairy as I am trying to put on weight. I am approximately 8% body fat. I work out between 3-5 times a week focusing on strength training and my training is what I would call smart as my girlfriend is a personal trainer and I am an avid listener of Robb Wolf. My issues are that I have been unable to put on muscle mass and my lifts have not been increasing despite being fairly new to working out (7) months. I went to the doctor and got my testosterone and thyroid checked out. My results were the following:
    TSH- 4.82
    T3- 1.5
    Thyroxine 8.0
    Testosterone 307!!
    Free Testosterone 50
    Testosterone, LC-MS-MS 315

    These results are troubling because I appear to have slight hypothyroidism and my testosterone is way to low for my liking. My doctor wants to put me on synthetic thyroid but after doing a lot of research I know this isn’t a cure for the issue only the symptoms. Even though I am 22 I do not grow alot of body hair especially on my face. I am writing to you because 1) I need to know what to have my doctor check for because he thinks to think that my results are fine and 2) what could be causing my symptoms. Also, just a side note I have been having a reoccuring pain in my left testicle and after seeing a specialist was told that it was an inflamed epididymis. I am concerned that this inflamation might have a connection with my hypothyroidism and low testoserone. I got an ultra sound (of my testicle) and everything was reported to me as being fine. Finally, to give full disclosure I do smoke weed about once a day and I know that could have an affect on testosterone. It is very frusterating to me to find out that I have a 300 level testosterone and it is frightening to learn that my thyroid might not be working. Just some more detail I have been smoking weed for about 5 years and In my “younger” days I would smoke what I would say would be a heavy amount. I use to drink alot to but since turning to paleo I have quit beer for the most part now only drinking at the most 2-3 times a month and not heavily (5-8 beers when i do). I did smoke cigarettes from the age of 17.5 until June of 2010. I have been cigarette free for a year now. Please point me in the right direction as far as what tests I should have my doctor run and what possible reasons could be causing my thyroid and testosterone levels. Also, I do not think that it is genetic because my younger and older brother have no problem growing hair and both of them were sprouting beards at very young ages. Also my dad said he had a beard at a very young age as well.

    Thanks you for everything you do and I hope you get the time to respond

  21. Matthew says

    Clarification on Greenpastures Fermented Cod Liver Oil: you said that this oil will oxidize when left out at room temperature, but this traditionally fermented oil is supposedly safe to store at room temperature. Is this actual fact or were you simply trying to say that Fermented CLO might oxidize when left at room temperature? Thanks for the quick clarification.

    • Chris Kresser says

      What I meant was that most cod liver oils are processed with heat, which can oxidize the fragile fatty acids. Fermented cod liver oil is cold-processed via fermentation, which doesn’t have the same effect. It should still be stored in the fridge.

  22. Aron says

    Incredible podcast. This one and Kurt Harris’ episode are classics. Can’t wait for part 2! Small complaint: the paper rustling and background noises are pretty distracting in some of your podcasts. Thanks for the amazing amount of info.
    Aron

    • Chris Kresser says

      Thanks for the feedback. I don’t have paper around me when I record them, so I can only assume it must be a guest. We’ll try to pay more attention to that.

  23. Daniel F. says

    Loved the podcast. I have sort of a simple question.

    Kresser states “The name of the game according to our current understanding is to support healthy LDL receptor site function and Iessen the amount of time LDL is floating around in the blood and to reduce the chance that LDL will oxidize which is related to that first goal. So you mention in one of your articles that there are no specific antioxidant’s we can take to specifically prevent that.”

    Two questions, and the second question will kind of lead us into the next topic I want to talk about. Is there a way for people to improve their LDL receptor function and what are some of the main things outside of diet and what we’ve been talking about that regulate receptor function?”

    Chris Masterjohn goes onto to explain the big picture and focuses on leptin resistance and say it plays a major role in LDL receptor activity.

    What are the best ways for your typical, healthy (no overt disease or symptoms) person to increase their LDL receptor site activity to promote quicker clearance of LDL particles? Is the best way for your typical person to increase LDL receptor activity/function is to focus on increasing leptin sensitive?

    The answer is usually eat a paleo type diet, but I was wondering if there were other steps/actions a typical person (not someone suffering from hypercholesterolemia) could take fairly easily to improve their LDL receptor site activity?

    • Chris Kresser says

      The main thing would be to improve thyroid function. For the average person, the first step would probably be determining iodine and selenium status and supplementing with both if necessary.

  24. Paleo Beginner says

    Hi Chris,
    I have been following the Paleo diet for a month or so and loving it.
    The thing is that i am muslim and our month of fasting (Ramadhan) is starting in August. The fasting starts an hour or so before sun rise and end with sun down.
    I used to load up on slow digesting carbs in the morning so that i have energy till late afternoon at least. Do you have any suggestions regarding what i can have in the morning that is slowly digested and can provide energy for a long time.
    I was thinking of drinking Casein Protein shakes but i have heard of its potential of causing GI irritation/Leaky gut.
    I dont have any medical conditions (that i know of).
    Thanks for your response.

  25. Paleo Beginner says

    Also love the podcast and looking forward to Part two. Like many of the commentators above i am curious about finding out ways to improve LDL receptor activity.

    Also wanted to ask what your opinion is regarding hormone therapy in increasing LDL particle size or even improving LDL receptor activity. Dr Davis likes to use them alot in his Track Your Plaque program.

    Thanks

  26. Roger Fisher says

    I’ve been on a Paleo diet for about 18 months and my LDL has risen from about 100 to 176 (I guess LDL receptors are doing a poor job?) while my HDL/Total C has increased from 2.4 to 2.7. My Lp(a) is 25. My doc tells me that the Lp(a) and LDL values both indicate high risk of CVD, and that together the risk goes up “exponentially”. How would you view these numbers; and any guide on bringing LDL down (doc wants me to eliminate sat fats and eggs). Thanks.

  27. Chollie says

    I’d kill for your numbers. My total Cholesterol went up as high as 376, now ‘down’ to 308. Total/HDL-C ratio was 4.6, now 4.9. I never had myself tested before going low-carb/paleo. In between these readings, I got my TC down to 274 but with a Total/HDL-C ratio of 5.3. This I achieved while cutting my fat intake during a phase where I was trying to lose most of my excess bodyfat. Now down to about 7-8%, so very lean and very fit and no health issues at all.

    I’ve been supplementing with Iodine, Magnesium, Fish oil/Cod liver oil, Vitamin C, Vitamin D, Calcium, while Selenium and Copper I get plenty from my multivitamin. Also, I switched from eating mostly chicken to mainly eating beef, added coconut oil (2 tbsps a day), eat lots of salad veggies and occasionally cauliflower, okra, spinach, etc. Recently added back some starch in the form of a baked potato post-workout. Also, I eat a serving of sardines everyday for some natural omega-3. The last test was before I added the potato and sardines, but I’d already been doing everything else for at least a couple of weeks, yet my TC rose from 274 to 308.

    The lipid profile doesn’t make sense, or if it does, I’m going to die in the prime of my life (I’m 27). LDL has not been measured, but the calculated value was as high as 286, now down to 215. Lowest it got was 202.

  28. ben says

    I thought the cholesterol found in the brain always is manufactured by the brain, due to the blood-brain barrier.

    But in the podcast, it’s mentioned that the liver / intestines produce XDL so that it can transport nutrients (fat soluble vitamins) and cholesterol *TO THE BRAIN*!

  29. Rob Ehite says

    I’m a bit late to the party, but i have to say Chris M come up with some great info in this. It has revolutionised my way of understanding how cholesterol (or more correctly, lipoproteins) may cause CV disease.

    It’s a shame the interview was marred by some extremely irritating paper clicking, shuffling, drawer-closing, and door slamming in the background, which at times made it difficult to concentrate on the conversation.

    Chris M, you said that LDL receptor activity is dictated by thyroid activity, which is dictated by leptin activity. A quick search on PubMed did indeed show several animal studies that indicate this connection.
    I read Lyle McDonald’s ‘Bromocriptine’ book a while back and he said dopamine agonists like bromocriptine and cabergoline (which actually appears to be a safer and more effective drug in the long run) simulate leptin by binding to leptin receptors to trigger similar responses as leptin would. Therefore, do you thing dompamine agonists like bromocriptine and cabergoline maybe effective in optimising LDL receptor activity? A few studies in obese humans have indeed shown administration of dopamine agonist drugs do lower circulating LDL, so that would seem to support the idea.

  30. Adam Kirby says

    Hi Guys,
    Very interesting topic. Could someone please help me understand my numbers? Do I need further blood work due to my present numbers, and if so what am I looking out for? I’m a 37 yr old male, 5.8, 7.5% BF, 160lbs, 29-30 waist size, exercise regularly. Been on a paleo type diet for about a year now. I’m gonna give you all my numbers from before I switched from a high grain high protein low fat diet to the paleo diet I have been on for around a year now.

    High Grain High Pro/low fat diet #’s

    Total=200
    HDL=64
    LDL=99
    Trig’s ?

    6 months into paleo diet

    Total=237
    HDL=72
    LDL=122
    Trig’s=30

    12 months on Paleo diet

    Total=270
    HDL=79
    LDL=174
    Trigs=26

    Thanks for your time!
    Adam

  31. Arjun says

    What is the effect of 30ml Alcohol ( Brandy) on daily basis for Heart & Cholesterol…. is it beneficial or harmful ?

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