Reevaluating Cholesterol and Its Effect on Our Health, with Marit Zinöcker
In this episode, we discuss:
- Setting the stage: Marit’s LDL cholesterol research
- The diet-heart hypothesis
- Why saturated fat affects people differently
- The new HADL model explained
- The genetic and evolutionary response to saturated fat
- Why we should be skeptical of the length of time in a clinical study on LDL cholesterol
- The role of inflammation and gut microbiota with high LDL cholesterol
- How this hypothesis can be considered in a clinical setting
- Criticisms of the HADL hypothesis
Hey, everybody. This is Chris Kresser. Welcome to another episode of Revolution Health Radio. This week, I’m really excited to welcome Marit Kolby Zinöcker as my guest. She has a bachelor’s degree in food science and a master’s degree in nutritional biology. She worked in cancer research for several years before she turned to teaching, and she’s currently working as a college lecturer teaching nutritional science and medical biology in Oslo, Norway.
I’m really looking forward to this conversation because one of the most common questions that I have gotten as a Functional Medicine practitioner over the last 10 years is whether high cholesterol is always a problem. A lot of people switch to a low-carb or even ketogenic diet to lose weight, improve their metabolic health, and they might find that their [low-density lipoprotein] (LDL) cholesterol or LDL particle numbers skyrocket when they do that. And they are, of course, curious about whether that is as much of a problem as their doctor and the mainstream medical establishment would hold.
And, we haven’t really had a good answer to that question. I’ve talked about it on lots of previous podcasts, and I’ve written a lot about it. But what I’m really excited to talk to Marit about is a new theory that she and her colleagues have developed, which would suggest that, at least in some cases, high cholesterol and high LDL particle number may actually just be an appropriate physiological response and not pathogenic. In other words, they would not confer any additional risk of cardiovascular disease.
So I know this will be of great interest to a lot of you. And I’m fascinated by the theory. They’ve published a paper on it, and we’re going to be talking all about the paper and the theory itself. So, without further delay, let’s dive in.
Chris Kresser: Marit, thank you so much for joining me on the show. I’ve really been looking forward to this conversation.
Marit Zinöcker: Thanks for having me on your podcast, Chris. I’m looking forward to it, too.
Chris Kresser: So where are you joining from?
Marit Zinöcker: I’m joining from my office at the college I work at in Oslo right now.
Chris Kresser: In Oslo. And that’s in which college? I couldn’t pronounce it, so I didn’t read it in the intro.
Marit Zinöcker: It has a Norwegian name, it’s called Bjørknes University College.
Chris Kresser: Bjørknes, okay.
Marit Zinöcker: It’s a private college.
Setting the Stage: Marit’s LDL Cholesterol Research
Chris Kresser: We’re going to be talking about a topic that’s of great interest to many of my listeners, which is whether high LDL cholesterol, a high number of LDL particles in the bloodstream, is always a pathological process that contributes to heart disease. This is, in fact, probably one of the top three concerns that I’ve encountered in my professional career as a Functional Medicine clinician. It’s one of the main reasons that people come to see me; it’s one of the burning questions that people tend to write in with or leave on the blog or ask in the podcast questions submission.
[A] very common scenario is somebody goes on a low-carb diet to address metabolic conditions, lose weight, improve their blood sugar, etc., and their LDL cholesterol skyrockets, their doctor freaks out, tells them they need to go on a statin, and then they freak out and they come to me, or try to find at least a second opinion or another explanation for why that could be happening. Because often, in that scenario, they feel so much better in every other way. They’ve lost weight, their blood sugar’s come down, their inflammatory markers have come down, [and] everything else has improved across the board.
And so, intuitively, it doesn’t make a lot of sense to them that something that would improve so many other processes in the body would then lead to such a dramatic worsening of their cardiovascular disease risk. So you have developed a model that could potentially explain a non-pathological reason for LDL cholesterol increasing in some of these situations, which we’re going to spend the remainder of the podcast discussing. But before we do that, maybe you could just talk a little bit about your background and how you got interested in this topic in the first place. Because this is one of the great sacred cows of nutritional science, and you’re definitely challenging the status quo here. And as we’ll discuss, there’s already predictably been some pushback and critique of the model from people who are still convinced of the diet-heart hypothesis and its validity. So what made you decide to take on this challenge?
Marit Zinöcker: This model was really born out of frustration from not being able to explain to my students what was going on when people would change their diet, and then they would change their intake of dietary fatty acids, and then cholesterol would change. And that intuitively doesn’t make sense, right? If it was cholesterol that people were [eating], and then the intake of cholesterol levels [were] changing, and then the cholesterol in the blood would change, that would make sense. But this just doesn’t make sense.
So I had students asking me that question, and, of course, I asked myself that question: why does this happen? And we see, of course, as we know, and probably many of your listeners know that eating a lot of saturated fatty acids will increase on average the LDL cholesterol, and then polyunsaturated fatty acids will decrease on average the LDL cholesterol. But we didn’t have an explanation for why that happened. And every time I was teaching this topic, I would just go down these rabbit holes of research, and [try] to find the answers. And I couldn’t really believe that no one had described these dynamics and what really happened at a molecular level, because an increase or a decrease in these particles means a change in [the] number of molecules. I couldn’t find an explanation, and I thought I would. I had to be completely useless because I couldn’t find those papers and I couldn’t find it in the textbooks, and it was like blank pages. And I was so frustrated with this, I just started trying to figure it out myself.
Chris Kresser: Yeah.
Marit Zinöcker: Yeah.
Chris Kresser: Well, kudos to you for doing that. Because what is the typical response in that situation is just to assume that there must be an explanation because everybody else is going along with this. So it must be something that either has been missed, or it’s unknowable, or maybe we don’t even really need to dig deeper there. Because this theory has been around for so long, it must be correct. So it’s not really useful to question it, which just blows me away, because the whole purpose of science and scientific inquiry is to question our hypotheses and in some ways try to prove them wrong. That’s how you make progress in science.
But I think because of some of our basic human tendencies, like groupthink, it becomes a real problem where we don’t want to be on the outside of a particular group, most of us at least. Because from an evolutionary perspective, that was risky. If we set ourselves apart from what the rest of the group was doing, our chances of survival were less, and even though that’s not the case anymore for physical survival, probably, it’s still a big risk to challenge the dominant paradigm. So again, kudos to you for being willing to do that.
In this episode of RHR, I talk with food scientist and nutritional biologist Marit Zinöcker about new research regarding the #HADLmodel, which challenges the diet-heart hypothesis and the mainstream approach to reducing cholesterol, preventing heart disease, and defining a “healthy” diet.
The Diet-Heart Hypothesis
Chris Kresser: Let’s start with defining some terms, because we’re going to be throwing around some acronyms and some terms, and I don’t want to assume that everybody knows what we’re talking about. So let’s start with the diet-heart hypothesis. We’ve already used that term a couple of times in this discussion, and I think most people are familiar with what it is. But let’s tell them specifically what the diet-heart hypothesis refers to because this is what your model is directly challenging.
Marit Zinöcker: Yeah, sure. The diet-heart hypothesis is resting on this three-step reasoning. And the first step is that a diet high in saturated fatty acids will, on average, increase LDL and total cholesterol. And that’s been shown in countless studies. And then the second step is the association between an elevated LDL cholesterol in the blood and atherosclerotic cardiovascular disease, which we can call cardiovascular disease for simplicity.
Chris Kresser: Or even CVD. We might throw [in] that term, CVD standing for cardiovascular disease. We’re going to omit the atherosclerotic part because that’s implied. Okay, so go ahead. That’s step two.
Marit Zinöcker: So that’s step two, and that’s well-documented, as well. And then we do this logical reasoning that since one is true, and then two is true, then a high intake of saturated fatty acids will lead to CVD.
Chris Kresser: Right. That’s a logical induction; A equals B, B equals C, A equals C.
Marit Zinöcker: Yeah.
Chris Kresser: Yeah.
Marit Zinöcker: Exactly. So that’s the diet-heart hypothesis.
Chris Kresser: Okay, so that’s the diet-heart hypothesis. And this is, of course, what we’ve been told for at least 60 years. It’s served as the underpinning of the dietary guidelines in the [United States] and in most other countries in the world. It led us down the path of egg white omelets, and boneless, skinless chicken breasts and steamed broccoli, and bagels with no cream cheese, and yeah, low-fat everything. And that’s, I think arguably over the last 10, 15 years, that’s shifted somewhat, and there [are] changing attitudes about that, at least in the general public.
But, what are some of the shortcomings of this hypothesis? We could spend several podcasts discussing the shortcomings, but maybe just from a 30,000 foot view, what are the biggest glaring issues with the diet-heart hypothesis?
Marit Zinöcker: So, if we go back to step one, these are average numbers, and those averages don’t really fit that many people. So, if we look at these actual interventions, because there are loads of interventions having been done, you can see that there’s a huge variation in response. You give the same type of, same amount of saturated fatty acids to lots of different people, and they will respond very differently.
And for instance, there was this Norwegian study on nutrition students published a couple of years ago where they saw, they were put on a ketogenic diet with a very high intake of saturated fatty acids. And the response varied from [a] 5 percent increase to [a] 107 percent increase. And that’s typically what you see. And so you will see differences between individuals; you will see that men and women tend to respond differently, even though there aren’t really that many studies in women alone. You will see seasonal variations to these types of responses. And there are loads of…
Chris Kresser: And you’ll see temporal variations, too, which we’re going to talk about later. Meaning if you measure a week after they start the ketogenic diet, you’re going to see very different numbers than if you measured two months after they’ve been on a ketogenic diet.
Marit Zinöcker: Yeah. And also, there are differences between healthy people and unhealthy people; they will respond differently. So that’s some of the problems with step one. But there’s also a bigger problem with step one that we talked about in the beginning, that we don’t know the mechanism. So we give advice based on changing these dynamics, and we haven’t understood the biological mechanism. And that’s pretty interesting, if you ask me.
Chris Kresser: Yeah.
Marit Zinöcker: So those are a few of the shortcomings with step one. And then there’s step two, and, of course, we know these associations that high LDL cholesterol is associated with CVD. But not everyone with a high LDL gets problems. So that’s …
Chris Kresser: And not everyone who has a heart attack has high LDL cholesterol on the flip side.
Marit Zinöcker: Exactly. Yeah. And then there’s step three, and, of course, that’s one of the big problems; no studies have shown this causality. It just hasn’t been demonstrated.
Chris Kresser: Yeah, I want to linger on that for a second, just to make this abundantly clear to people. [For] the whole step, there’s been a stepwise chain of reasoning where consuming more saturated fat leads to elevated cholesterol, [and] elevated cholesterol is associated with heart disease; ergo, consuming saturated fat causes heart disease. But what you’re saying, and what I’ve written about ad nauseum now and talked about in numerous podcasts, Joe Rogan, etc., is that there are no convincing studies that demonstrate that causal relationship between saturated fat intake and heart disease.
When they’ve removed serum cholesterol as the middleman, so to speak, or as the mediator or the mechanism, and they just looked directly at the relationship between saturated fat intake and cardiovascular events, they see either, and correct me if you disagree, either no increase in cardiovascular events, or in the case of stroke, I’ve seen large reviews that actually show a decrease in stroke incidence with a higher intake of saturated fat.
Marit Zinöcker: Yeah so, and I think you also went through all the evidence with Zöe Harcombe in previous episodes. It’s very clear that it doesn’t really add up. So I think that when something doesn’t add up, we have to go back and look at this reasoning, and maybe we just misunderstand something along the way.
Chris Kresser: Right. That takes some scientific integrity and curiosity, which, fortunately, there are still many scientists out there who possess that. And unfortunately, I think again, our basic human nature tends to work against us in some cases there.
Why Saturated Fat Affects People Differently
Chris Kresser: So let’s talk a little more about individual differences with how saturated fat intake affects blood lipids and other things physiologically. As a clinician, I can certainly attest to this myself, just anecdotally. I see dramatic differences in the response to varying levels of saturated fat intake. If somebody is overweight, for example, and their LDL particle number is high because of, they have high triglycerides and the liver has to make more LDL particles in order to transport the same amount of nutrients around the body, including cholesterol, [a] ketogenic diet can actually lower LDL in those people in my experience. On the other end of the spectrum, I’ve seen people go from total cholesterol of 175 to 350 in a relatively short period of time, just from switching to a ketogenic diet. So what are some of the factors that determine this variable response in individuals?
Marit Zinöcker: Yeah, we know that there are fixed differences. We know that there are, of course, genetic differences. So those can also, loads of different genes can explain some of that variation. And probably the habitual diet, which is very related to what we are going to talk about or talking about today. And also, like you say, in people who are not metabolically healthy, there are loads of things that can go wrong, and that can interfere with the lipid metabolism. So, I guess there are many different factors that influence the specific response in an individual. But they still don’t explain what happens at the molecular level. I think that’s where the HADL model is useful. And then if we could remove some of that noise, then we could figure out a little bit more what’s the significance of genetics?
Chris Kresser: All right, so we’re getting to the point where I’m going to ask you to introduce the HADL hypothesis and break down that acronym. But I want to do one more thing to set the stage, which is, we know from studies that saturated fat intake doesn’t increase the synthesis of cholesterol nor does it increase or speed up the absorption of dietary cholesterol. And then on the flip side, we know that increased intake of polyunsaturated fatty acids (PUFAs) doesn’t cause a decrease in synthesis or absorption. So the key question now, and this is what you’re trying to answer with the HADL hypothesis, is when someone does eat a high saturated fat diet, where do all the additional cholesterol particles or cholesterol molecules that end up in the LDL particle come from? If it’s not from increased synthesis, it’s not from increased absorption, where are they actually coming from?
Marit Zinöcker: It’s magic.
Chris Kresser: Well, that’s what we’re going to spend the rest of the time answering, right? But that’s really the fundamental question that you were trying to answer in developing this hypothesis.
Marit Zinöcker: Absolutely. And I think that’s the million dollar question. And I’m a little bit confused why more people have [not] asked this question, because it’s so central for the whole cholesterol fight.
The New HADL Model Explained
Chris Kresser: Right. Well, we’ll get to, you have the benefit already of, I say benefit because I think it’s really useful and helpful for a theory or a hypothesis to be challenged, because it helps us to get even more clear on parts of it that may not have been as clear. And so we can talk a little bit about one of the responses that you’ve received, and their explanation for what’s happening here, which didn’t seem satisfactory to me and I don’t think is satisfactory to you. We can talk about why, but we’re getting a little ahead of ourselves here. Let’s first talk about what is, give us an overview of the HADL hypothesis, including what that acronym stands for and how it addresses this question that we just asked as well as the other shortcomings of the diet-heart hypothesis.
Marit Zinöcker: Yeah, sure. So the HADL model stands for the homeoviscous adaptation to dietary lipids model. So that doesn’t exactly roll off the tongue …
Chris Kresser: That’s why we have the acronym. HADL is better, and we’ll be using that throughout the rest of the show.
Marit Zinöcker: Exactly. So to explain the model, we need to talk a little bit about the fatty acids that we eat. And we need to talk about cells and cell membranes. Because when we eat different types of fatty acids, some of them will end up in our cell membranes. And of course, we have, I don’t remember how many but trillions of cells in our body. So there are loads and loads of cells that will receive these dietary fatty acids. And the type of dietary fatty acids that we eat will change the fluidity of those cell membranes. And that fluidity is crucial for the function of those cells to keep all the proteins in order that do all this, control everything that goes in and out of the cells and cell signaling and all these functions.
So what we’re posing is that if you’re eating a diet rich in polyunsaturated fatty acids, PUFAs, as we call them for simplicity, are making the membrane more fluid because these molecules kink at the double bonds. They can’t pack that tightly together.
Chris Kresser: Yeah, for the listeners, just think of sunflower oil or safflower oil. It’s liquid at room temperature, whereas a saturated fat, like butter or coconut oil will be solid. So you can think about that happening in a cell membrane to give you an idea of what’s going on.
Marit Zinöcker: Yeah, exactly. So if you’re eating a lot of PUFAs, then your cell membrane will become more fluid. And the cell needs to adjust this. And the way it does that is by incorporating more cholesterol, because cholesterol works as a, it sort of restricts the movement in the membrane. And of course, that cell needs to get that cholesterol from somewhere. So now it will, it can both increase its own production, and it will do that, but it will also increase the uptake from the bloodstream from the LDL particles that travel around the blood, and yeah,
Chris Kresser: So, let me just stop you there, because I want to make sure everyone’s following this. For those who don’t have a background in biology or nutritional science, it can be tricky. So what you’re saying there is when somebody eats more PUFA, the cell membrane becomes more fluid. And then the cell needs to bring in more cholesterol, because cholesterol has a stabilizing effect on the membrane. And one way for that to happen is the production of more cholesterol.
But the other way for that to happen is that the cell will incorporate cholesterol from, will take it out of essentially, LDL particles that are normally just carrying around cholesterol in the bloodstream. And so what you would expect to see in that scenario is a decrease in the amount of cholesterol carried by LDL particles. And that’s exactly what you measure on a standard lipid panel. When you see LDL cholesterol, that’s what it’s referring to, how much cholesterol is being carried by the LDL particles. And in this scenario, it’s going to be less because the cell membranes are taking it up to compensate for that extra fluidity from the high PUFA intake.
Marit Zinöcker: Yes, exactly. So what we’re doing with this model is shifting the view from not just looking at the lipoproteins in the blood, but we’re looking at the whole body cholesterol.
Chris Kresser: All of the other cells and how all of the other cells use cholesterol.
Marit Zinöcker: Yeah, exactly. So these cells will then increase the LDL receptors on the surface and take up those particles to make sure they get enough cholesterol. And we also know that in that situation, we know from studies that the cells will take in the LDL particles, they will transport the cholesterol toward the membrane first to meet the needs of the membrane, and then the rest will be transported back into the middle of the cell to deregulate production.
Chris Kresser: Interesting. So that’s also important to understand those mechanisms because it indicates the priority system, essentially.
Marit Zinöcker: Exactly, yeah.
Chris Kresser: The fact that [LDL particles] get incorporated into the membrane first means that this is a high priority biologically, and that also, I think, lends credence to this hypothesis, because if that’s what’s going on, it means that that’s an essential function of cholesterol. And cholesterol so often has just been seen as bad, right? As something that if we could get it to zero, we should.
Marit Zinöcker: Absolutely.
Chris Kresser: Which, of course, any scientist who studies cholesterol knows that we would die if that happened. There’s Smith-Lemli-Opitz syndrome, a genetic condition that causes extremely low cholesterol levels, which can be fatal. But the sort of prevailing attitude, I think, has been that cholesterol is useless, and only serves the function of killing us, giving us heart attacks, clogging our arteries, giving us strokes, etc. But you’re pointing out here with this model that no cholesterol has essential functions, in this case, in terms of regulating cell membrane fluidity and structure, and that we’ve totally ignored those functions in how we understand dietary intake of saturated fat and its effect on our health.
Marit Zinöcker: Yeah, absolutely. And in all the years I’ve been studying and teaching nutrition and talking to other nutrition professionals, no one seems to be talking about the membranes.
Chris Kresser: Right. It’s hard to imagine a more important function, right?
Marit Zinöcker: Yeah.
Chris Kresser: Like cells run everything. No cells, no life and no membrane, no cell, right?
Marit Zinöcker: Yeah.
Chris Kresser: The cell membrane is a critical part of the cell. So let’s look at what happens in reverse. What you just described is why, in general, because again, we know there’s lots of interindividual variation, but what you just described explains why people who go on a high-PUFA diet typically, on average, have lower cholesterol, lower LDL cholesterol levels.
But let’s look at, so the flip side, the opposite of that, when somebody goes on a high saturated fat diet, it’s basically everything in reverse. But why don’t you just go through that so it’s clear for everybody.
Marit Zinöcker: Sure. So this is what we’ve seen in lots of those interventions that are fundamental for the diet-heart hypothesis, right? So if a person is eating, or if given an intervention with a lot of saturated fatty acids, and then usually this is done with subtracting the PUFAs.
Chris Kresser: Right.
Marit Zinöcker: They typically don’t give them at the same time, so then you give just the saturated fatty acids. So now the opposite will happen. There won’t be a lot of PUFAs in the membrane, so the membranes will be less fluid. And when they’re less fluid, they will pack more tightly together. And they won’t need that cholesterol to stabilize the membrane. So they will have to get rid of the cholesterol to make sure that the membrane’s not too stiff, because it has to be just the right fluidity. And the cells will do that by directing the cholesterol in the cell, and then, of course, too much cholesterol in the cell is toxic to the cells. And now it needs to get rid of the cholesterol. It would do that by increasing the transportation out from the cell by specialized transporters. This is what we call cholesterol efflux. And this cholesterol will be received by the HDL particle. And this is why we say that the HDL particles tend to go.
Chris Kresser: Increase as well with a high saturated fat intake. Yep.
Marit Zinöcker: And also because now the cell doesn’t need more cholesterol; it has too much cholesterol. It will downregulate it on its own production, and it will also downregulate these LDL receptors, [and] will stop taking up from this [crosstalk 00:27:19]. That’s when LDL rises.
The Genetic and Evolutionary Response to Saturated Fat
Chris Kresser: I want to pause for a moment and point out that earlier, we talked about some of the factors that lead to different responses to saturated fat in the diet, and one is genetic. And within that genetic category, one of the main if not the primary response is a downregulation of the LDL receptor. We know that some people genetically have fewer LDL receptors or less active LDL receptors. So that’s already a well-established mechanism for why cholesterol would be higher in certain individuals. This is a different explanation, or at least a different reason for how that, when that mechanism is in effect. Instead of being a genetic cause, it’s related to diet; it’s the body responding in a natural way to changes in dietary saturated fat intake and using the LDL receptors, one of the mechanisms, to regulate cholesterol levels in the cell membrane and in the cell.
Marit Zinöcker: Yeah, and this, of course, if we think about this in an evolutionary way, this is a huge benefit to us because we’re an omnivore species and we need to adjust these cell membranes with [a] very bearing intake of foods and sources of fat. So yeah.
Chris Kresser: Right. So if you’re an Inuit living in the Arctic, and you’re eating seal blubber and other sources like other fat, other types of fat, both saturated, you look at ancestral diets. This is a fundamental principle of the ancestral hypothesis, right? It’s not so much about what the diets shared in common; it’s what they didn’t, or what they included is what they didn’t include, right? Because we see evidence of people being healthy on very high intakes of saturated fat. The Maasai come to mind, right? And then we see people being healthy on [a] very high intake of carbohydrate, like the Tukisenta who ate mostly sweet potatoes and some insects and not much else. And one way of explaining that, which is what you just said, is that the body has multiple mechanisms for adjusting and meeting its own biological and biochemical needs with widely varying intake of macronutrients.
Marit Zinöcker: Yeah, absolutely. And we can even move from these different food environments, and we also have probably done with seasonal variations and these things. But you could live with the Maasai and eat like the Maasai, and then you could go to Kitava Island and eat like they did, and the body will simply adapt. So these are adaptive mechanisms. So this model really explains the changes in cholesterol levels in the blood as necessary and adaptive mechanisms to maintain cell function, even with changing sources of fatty acids. And there’s constantly this exchange going on between the blood and the tissues to make sure that works perfectly.
Why We Should Be Skeptical of the Length of Time in a Clinical Study on LDL Cholesterol
Chris Kresser: Let’s talk about something that I mentioned earlier, which is the influence of time on all of this. We can launch into it with a clinical scenario. Sometimes someone will switch; they’ve been on a lower-fat diet for a while, and they switch. They hear about a ketogenic diet and they want to try it, and they switch to it, and their lipids, their LDL goes through the roof. Why should we be skeptical or cautious of interpreting studies on dietary fat intervention that are two weeks long or even two months long? And what have longer-term studies on the impact of dietary fat shown?
Marit Zinöcker: Well, the problem is we don’t really have that many long-term studies. There’s really a lack of studies having the test of the effect of a high [survey] intervention for a long time for more than just a few weeks. There is one called Carb Funk. No, sorry, it’s the wrong one. It’s called Fat Funk. And they have data from eight weeks, four weeks, eight weeks, 12 weeks, so that’s on a low-carb diet. And they see initially that the LDL goes up, but then they see at 12 weeks, it starts to go down again. So this might be like long- term downregulation when the body has reestablished homeostasis. But we don’t really know that, and we need more studies to be sure [of] what’s going on in the long term.
I’ve also seen long-term results from ketogenic diets where the LDL levels don’t really go down, but the phenotype changes. They go from the small dense ones to the large ones. So there has definitely been something going on. But I think this might also be different in unhealthy and healthy individuals. It might be that in metabolically unhealthy individuals, you would see initially a rise in LDL. And then as soon as their metabolism gets better, it will go down again and then establish at the level that’s right for that individual. I think if everything else is normal, all the other parameters are good, then that LDL level is right for that person possibly.
Chris Kresser: Yeah. This is one of the reasons, unfortunately, there’s not. These studies are expensive, especially if you’re doing metabolic ward studies. And if there’s no drug discovery or development process at the end of that, it’s hard to get that kind of study funded.
Marit Zinöcker: Absolutely.
Chris Kresser: And if you’re a statin drug manufacturer, you’re not going to have a whole lot of interest in funding that study. Because the outcome is not really going to be beneficial to you.
The Role of Inflammation and Gut Microbiota with High LDL Cholesterol
Chris Kresser: But let’s talk a little bit more about the concept of, that you’ve just introduced, which is that, and we touched on it before, one of the reasons for the variable responses to dietary fatty acids is the metabolic health or other aspects of health of the person in question.
And two things stood out to me from your paper that were quite interesting and in alignment with other research that I’ve done or that I’ve seen [are] two of those factors that determine how people respond to dietary fatty acids are inflammation and gut microbiota. And I would say the prevailing paradigm or hypothesis right now is that you gain weight and inflammation happens as a result of that. Or even that inflammation is a cause, a kind of independent and distinct contributing factor to cardiovascular disease, that together with high lipids, makes it worse than if you just had high lipids at all. But one of your, if I understood it correctly, one part of your hypothesis is that inflammation may actually be a causal factor for having high cholesterol or high LDL cholesterol, which is something that’s fundamentally different [from] what has been proposed before.
Marit Zinöcker: Yeah, so, we definitely know that inflammation has the potential to affect lipid metabolism. It does affect other types of homeostasis like glucose homeostasis. And we know that inflammation can interfere with lots of signaling pathways, and I think we’re only starting to figure these things out. There [haven’t] been that many studies, but it’s well-known that in insulin resistance, inflammation is interfering with the function of the [Insulin] receptor. We know also from animal studies that inflammation can interfere with, for instance, pathways for satiety and breath regulation. We know that it can interfere with some neurotransmitters like serotonin, so it affects mood. And so it doesn’t seem completely far-fetched to think that inflammation could mess up some of the pathways important for lipid metabolism, as well.
We don’t know if it interferes with the uptake via the LDL receptor. I haven’t seen any evidence [of] that. But I have seen, at least there are animal studies showing that inflammation will inhibit some of these nuclear receptors that are involved in lipid homeostasis. For instance, those efflux transport proteins that we talked about earlier. They will, and so inflammation will probably, can probably explain why HDL is low in metabolically unhealthy people. So that’s simply something we know from animal studies. That could probably explain this observation in humans, if it proves to be the same. So I think the role of inflammation in lipid metabolism is still in its infancy. But there’s definitely something going on there that we need to figure out.
Chris Kresser: Right. And the gut microbiota, I think this is, I’ve seen quite a bit of research on this topic. But what do you think is the mechanism here, where if you have dysregulated gut microbiota, maybe from taking too many courses of antibiotics, or any of the other multiple factors that affect the gut flora, how might that impact lipid metabolism?
Marit Zinöcker: That would be the link with the inflammation, or it could at least explain some of the low-grade inflammation that’s seen in people with metabolic disorders. We know that gut microbiota can induce inflammation in humans. And they’re all probably, there are loads of dietary factors that can influence inflammation, gut inflammation that can be transferred to the whole, to the circulation and work at a systemic level.
Chris Kresser: Right. So you have endotoxins, maybe lipopolysaccharide, that are produced in the gut and then cross through the permeable gut barrier, end up in the bloodstream, and then provoke an inflammatory systemic, inflammatory low-grade response.
Marit Zinöcker: Not just through the barrier, [but] they also enter the chylomicrons. So they also travel by the normal uptake mechanism of lipids, and that’s seen in studies, but in obese people. And first, they have more bacteria growing in their small intestine, and then also more of these bacterial products like the [lipopolysaccharide] (LPS) will be taken up by the chylomicrons and will enter the circulation and increase the endotoxemia after a post-[inaudible 00:40:01].
Chris Kresser: Right. So you have multiple, you have the pathological mechanism per se if that person has intestinal permeability, like an inappropriately permeable gut barrier, because our gut barrier, of course, has appropriate permeability; that’s how we extract nutrients from the food we eat. But then you have a very normal physiological mechanism, which is the normal uptake of chylomicrons. But in the case where there’s overgrowth of bacteria in the small intestine where that happens, then those bacteria hitch a ride, so to speak, in the chylomicrons and can produce endotoxemia and inflammation, even when there’s no leaky gut or intestinal permeability present.
Marit Zinöcker: Yeah. So I think we need to ask the question, what leads to a lot of LPS producing bacteria in the gut. And we need to make sure that we eat diets that won’t facilitate this growth of bacteria and this transfer of bacterial products into the bloodstream.
Chris Kresser: Right.
Marit Zinöcker: And in that context, dietary lipids are less important. They can work as a transport molecule sort of. But what causes the bacterial overgrowth in the first place and like pro-inflammatory gut microbiota? Those are different factors. So that’s probably …
Chris Kresser: Acellular carbohydrates.
Marit Zinöcker: Yes, exactly. So it’s the refined carbohydrates, and also we know that some additives can also induce inflammation in the gut.
Chris Kresser: Right.
Marit Zinöcker: So maybe it’s time to ask if we have been barking up the wrong tree when it comes to prevention of CVD.
Chris Kresser: Certainly a lot of evidence pointing in that direction. And I think the HADL hypothesis is a phenomenal contribution to understanding the mechanisms behind that.
How This Hypothesis Can Be Considered in a Clinical Setting
Chris Kresser: Let’s talk a little bit about implications. What does this mean for the average person?
And one conclusion that emerges right away if you’re following all of the threads here is that, let’s say somebody goes on a high-fat diet, low-carb, ketogenic whatever, and they see an increase in their, let’s go back to the hypothetical person that I was talking about before, they see an increase in their LDL, but their C-reactive protein and interleukin 6 and ferritin, and other inflammatory markers go down, their blood sugar glucose goes down, their weight drops, their visceral fat decreases, [and] their blood pressure decreases. Everything else, every other marker that we know of that is an indicator of metabolic and cardiovascular health improves.
Let’s consider that scenario. And let’s say somebody else does the same intervention and their LDL also skyrockets. But in that case, all of those other markers don’t improve; maybe some of them even get worse. Maybe their inflammatory markers go up, [and] they don’t really lose that much weight. It’s just they might get some mix of improvement and worsening, but overall, not nearly, a lot of the other metabolic and inflammatory markers are the same or worse. Would you think that we should approach those two people in the same way?
Marit Zinöcker: Sort of a leading question. And I’m no clinician. We have to remind ourselves that this is still a hypothesis. So this hypothesis also has to be confirmed before we can draw any conclusions. But let’s say it holds water in the coming years, and I think that in that first scenario that you’re painting, I think there is no need for the doctor to freak out. There’s no need to go on a statin because of the elevation in LDL cholesterol, and all these factors that you mentioned. And it’s an indication that the body is really repairing itself. It’s re-establishing a normal homeostasis.
So it doesn’t really make sense that this one measurement is off and means something pathological. Why would it when everything else is, the body’s fixing itself? So maybe that’s part of that process. Maybe we should reconsider the role of the LDL particle in this way. And also, that’s a sign of a functioning body, that that person is able to adjust the amount of cholesterol between bloods and tissues in this situation.
Chris Kresser: Right.
Marit Zinöcker: Yeah, and also their response in healthy people. I think that the increase in LDL cholesterol from a lot of saturated fatty acids [is] a sign of a healthy response.
Chris Kresser: Right.
Marit Zinöcker: But the other person you’re describing, I’m not so sure what to do with [them], but we can’t rule out the possibility that in that situation, a sustained elevated LDL particle level might do something that it wouldn’t have done in a healthy body. But I don’t know. What do you think?
Chris Kresser: Yeah, I think I agree. We still need more information, more data to try to figure this out. But that’s basically how I have approached things as a clinician for some time now. The way I explained it to patients is, you have to consider the net effect of an intervention. So if you’re prediabetic, or even diabetic, and you’ve got metabolic syndrome, you go on a ketogenic diet, and it improves 99 percent of the markers and objective[s] and things that we can measure as indicators of your health, and also subjective measures, which I don’t discount. And one marker gets a lot worse, then to me, the net effect of that intervention is still overwhelmingly positive. So I would encourage that as an intervention for someone in that situation.
In the second scenario, the net effect is much murkier. Maybe the net effect was either neutral or actually even negative, if they didn’t really lose significant weight, their LDL went up considerably, their metabolic markers maybe changed a little bit, but their inflammatory markers went up. To me, that’s less of a slam dunk. And maybe in that case, I might try something like a protein-sparing modified fast, or I might try more fasting or a potato hack or some other strategy that might, and to test that out and see if that leads to weight loss or changes in metabolic markers.
And so I think, unfortunately, because of the lack of research that you mentioned before, and maybe I’m a little skeptical or pessimistic here, I don’t think we are going to have these studies anytime soon that answer this question. I hope I’m wrong. And I hope we do see these longer-term studies. The study I’d like to see, and I actually, I talked to Dr. van Vliet. I think you know, do you know his work? I could be pronouncing his name , Stephan van Vliet.
Marit Zinöcker: Yeah, I know him.
Chris Kresser: Yeah. So he is doing [a randomized controlled trial] (RCT) on the effects of saturated fat, but it’s going to be relatively short term, because again, doing a two-year RCT and metabolic word study would be ridiculously expensive. So for me, as a clinician, I think the only way in a very short term until we have that research is to just look at the net impact of the intervention and not get hung up on any single marker and consider health from a more holistic point of view. That’s how I’ve approached it.
Marit Zinöcker: Absolutely. I think that if our model proves to be correct, it might take a little bit of, well, it might make the ketogenic diet more, what’s the word?
Chris Kresser: Accepted? Palatable for clinicians?
Marit Zinöcker: Yeah, yeah.
Chris Kresser: They’re not going to freak out, like you said, when they see LDL go up. And we need therapeutic tools, as you pointed out in our email correspondence. One in three Americans now have prediabetes or diabetes. We have [a] 60 percent rate of, I think it’s actually 70 percent overweight now, and 42 percent are obese. We are desperate; we need help. We desperately need tools that can help reverse this, and ketogenic and low-carb diets have been shown over and over in studies to be effective tools. And so anything that could remove the barrier or resistance to implementing these in clinical practice is very welcome.
So I hope that you’re able to do the research that is needed, you and others perhaps to confirm this hypothesis and that it makes the difficult and arduous journey from the realm of research science to primary care. As you know, that’s a long road, and there [are] lots of obstacles on that road, and certain vested interests that are financially deeply invested in the current status quo paradigm that may not want the paradigm to change. But I think this is a really great first step in that direction.
Criticisms of the HADL Hypothesis
Chris Kresser: One last thing before we finish up. There was a letter, I forget what journal it was published in, it was in the same journal the study was published [in]. So that raised some criticisms of the HADL hypothesis. Since we’re running out of time, we don’t have time to go through each one. But maybe, if you could highlight either, you can choose what you think makes the most sense. Either overview of their criticisms and then your rebuttal. Or, a specific criticism that stood out or that you think was one of their primary arguments, and then the rebuttal to that.
Marit Zinöcker: This letter to the editor came from some people who work in groups where the diet-heart hypothesis is central to their work. So, of course, it probably didn’t resonate so well with them.
Chris Kresser: Yeah, exactly.
Marit Zinöcker: So the title of these letters are coming soon. They haven’t been published yet. But they will be published pretty soon, I think. They raised quite a few points, and some of them are not really relevant for or aren’t really in conflict with the models. So we chose not to respond to those. They raised the question though, for instance, the fluidity of these, how the dietary fatty acids will affect the fluidity of the membranes. So they say, like if this was related to the melting point, then you would see, then you would have, you would be able to predict the response in LDL cholesterol from the melting point of the fatty acid.
Chris Kresser: Exactly. How saturated or how unsaturated the fat is, yeah.
Marit Zinöcker: Yeah. And this is not what we see in intervention. So they say, this is sort of an objection to the model. However, what’s interesting is, or what our response was that these fatty acids aren’t just incorporated into the membranes. They’re incorporated in a very regulated manner. So the cell will modify them if it needs to adjust the fluidity.
Chris Kresser: Right.
Marit Zinöcker: So the longer ones that are typically stiffer, and that you would think would cause a certain effect, they are typically modified by adding double bonds before they’re incorporated into the phospholipids of the cell membrane. So that’s why you can’t really extrapolate from the melting point.
And another point they raised was the temporal issue. They said, this is not happening so fast. So if this is a regulation that the cell needs to do to function, that would happen really quickly, and we see these changes typically in a few weeks’ time. But there aren’t that many studies that attempt to have [that] tested. They haven’t really tested what happens after two days, after [crosstalk 00:54:07].
Chris Kresser: One day after, four hours after, etc., yeah.
Marit Zinöcker: Yeah, exactly. They typically just measure after two or three weeks. And then we assume that these changes happen after two or three weeks. But we do have some data from the cell cultures, where they load these cells with omega three fatty acids and they see they start immediately by exchanging their membrane lipids and adding more cholesterol. So we know this is going on in the cell culture, but, of course, we haven’t shown that this is going on in an organism. But it seems like this is happening a lot quicker than [crosstalk 00:54:49].
Chris Kresser: So that seems like a fruitful area of research that would be not excessively costly or difficult to do as a study. It’s a pretty clear question that you’re setting out to answer and [a] pretty clear path for answering it. So is that a plan of yours or any other research group that you know of at this point?
Marit Zinöcker: I don’t have a lab. I’m not connected to a lab. I would have to [crosstalk 00:55:18].
Chris Kresser: You’re more like a theoretical physicist or something like the equivalent. You need to hook up with an experimental, someone who can perform these experiments in the lab.
Marit Zinöcker: Absolutely. But of course, we’re hoping to see publications tagged with the HADL model in the upcoming years.
Chris Kresser: Great. Well, thank you so much, Marit. It’s been a pleasure to speak with you, and it’s really a fascinating hypothesis. And I hope that it continues to get the attention that it deserves because there are some real glaring issues with the diet-heart hypothesis that have been raised by many different people in many contexts over the years, and hundreds, if not thousands of papers that are critical of the diet-heart hypothesis. Definitely thousands, maybe even tens of thousands at this point.
So it’s not like you’ve just been working as a mad scientist in your office in Oslo, and coming up with this stuff on your own. This is building on the huge amount of research that has already raised questions, and you outline some of those in the three parts of the diet-heart hypothesis and the problems with each part. But the response so far seems to have been to just consider those as, to use Al Gore’s term, inconvenient truth, right? That they’re there, and we don’t know how to explain them. But they’re inconvenient, so we’re just not going to even try to explain them.
And what I appreciate about what you’ve done is you’ve actually peeled back that layer of the onion, and [are] really taking the time to try to explain those findings. And at least from my perspective, it’s a very sensible hypothesis with some good evidence behind it, and it certainly deserves more explanation and to be confirmed, or at least iterated on and improved in some way if it’s not accurate the way that you’ve outlined it. So hopefully, that will happen soon.
Marit Zinöcker: Yeah, and thanks. We hope that this will spark a better conversation on what we should eat, what are the best human diets.
Chris Kresser: Absolutely. And what I like about this hypothesis, as well, is I’ve from the beginning, when I first, all the way back to my first book in 2013, one of my mantras has always been there’s no one-size-fits-all approach and that the idea that there’s a single diet that is going to work for everybody is preposterous for so many reasons. And this is very much in alignment with that. Like that actually, there’s a way of explaining how high cholesterol might mean different things for different people in different contexts at different time periods. And that complexity and nuance in my experience is almost always more likely to be accurate than a very simple binary kind of explanation when it comes to the body.
Marit Zinöcker: Absolutely. And also, we need to consider the human adaptive biology when we study [crosstalk 00:58:36].
Chris Kresser: Right. There’s a lot, a lot, a lot of years of evolutionary wisdom that’s gone into those mechanisms, right? And it’s sometimes foolish to underestimate their sophistication.
So all right, well, thanks again. And thank you, everybody, for listening. Keep sending your questions in [to] ChrisKresser.com/podcastquestion, and we’ll talk to you next time.
This last May of 2021 was the 11-year anniversary of my podcast. Back in 2010 when I first started, podcasts were the Wild West! Hardly anyone had heard of them, even fewer people were listening, and only a tiny handful of us were producing them.
I’ve had a blast doing nearly 300 episodes of the show over that 11-year period. And lately, I’ve been thinking a lot about what I’d like to do with the show over the next 10 years. In some ways, I’m even more excited about podcasting today than I was when I started—and I’d love to ask for your input on how I can improve the show and make it even better and more relevant to your interests.
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