Welcome back, FoundMyFitness amigos. Today we try to answer, or at least explore, a big question in the world of health: does saturated fat cause heart disease? This is not an unreasonable concern given the fact that there have been several associative studies that have found a link between saturated fat and heart disease, which is no doubt a fat that is abundantly found in the typical American diet since it's richly found in staples like fatty beef, pork, butter, cheese, and other dairy products. And if you're in the United States and you're not at least a little bit concerned about heart disease, you may be asleep at the wheel since it's currently our leading cause of death.

As it turns out, however, the link between saturated fat and heart disease, like the link between meat consumption and cancer discussed in the previous episode entitled Does Meat Consumption Cause Cancer, may not be quite so straightforward. In 2014, this arguably oversimplistic narrative that saturated fat was the cause of heart disease hit a snag when a meta-analysis was published in the journal Annals of Internal Medicine. It looked at a There were 72 studies from 18 different countries, one of the largest to my knowledge, that explored this relationship to date. The result? They found that there was no evidence to support the notion that consumption of saturated fatty acids or levels of saturated fatty acids in the blood increased the risk of coronary heart disease.

So does it cause heart disease or not? What's important to realize is that these meta-analyses, both the one in 2014 and the ones prior, We're looking at observational studies, which don't actually establish causation. If we take a step back from the observational studies that are sort of sending us mixed signals and messages, and instead move our discussion towards what some of the randomized controlled trials are telling us, we may have a better chance of actually understanding what's going on. These types of trials are more useful for establishing actual causation and are considered a type of gold standard for clinical trials. Observational studies are great for noticing larger patterns, but the randomized controlled trials help us tease out what exactly is going on.

In 2016, In 2018, a randomized controlled trial came out in the American Journal of Clinical Nutrition involving 38 men showing that in comparison to a diet in low saturated fat and high in refined carbohydrates, a diet high in saturated fat and low in refined sugar and low in processed foods not only didn't seem to cause heart disease, something that might altogether be surprising happened. It led to reduced fat storage both in the liver and in the heart and was able to improve triglycerides, improved blood sugar and insulin sensitivity, and lowered blood pressure. All of these are factors that show a trend towards reductions in risk of heart disease. What's different? Maybe you caught it. That's right, low in refined sugar and/or processed foods.

This is very interesting for the simple reason that many observational studies looking at saturated fat consumption don't really bother to differentiate diets that may contain saturated fat but are otherwise low in refined sugar from the typical Western diet, which of course is loaded with both refined sugar and saturated fat. The refined sugar issue is a problem we're all very aware of. So let's talk about adding it back and see what happens. That's what these randomized controlled trials are for, right? Same journal, American Journal of Clinical Nutrition, but a few years earlier, published a study that's quite interesting.

In this trial, healthy, normal-weight young men were given 20 ounces of a sugar-sweetened beverage that was more or less similar to drinking like a can of soda pop for 3 weeks. In this trial, we see that the average LDL particle size began to lean towards a greater number of what are known as small, dense LDL particles. Moreover, a biomarker of inflammation known as C-reactive protein showed an increase between 60% to 100% over baseline. Clearly adding a bunch of refined sugar definitely has some biological consequences.

And if we pay attention to what's happening to the LDL in the presence of this big bolus of sugar our human lab rats were getting, We might get some answers to explain the situation with our observational studies showing inconsistent results in the context of saturated fat and heart disease. But let's first speak to the elephant in the room. A 60% to 100% increase in a marker for inflammation is downright alarming. If you've been listening to my podcast for a while, you're probably well aware of the high systemic inflammation underlies processes fundamental to basically all diseases of aging and even cancer, which is a disease of aging. I've even talked about recently how it likely undermines mental health and causes depression.

To understand what's going on with LDL though, we need a brief biology lesson. The difference between large buoyant LDL particles and small dense LDL may be lost on a few of you, and who can blame you? It's lost on quite a few clinicians as well, if we're being honest. Not all LDL cholesterol is created equal, and specifically not all LDL confers the same risk of heart disease. LDL can be large and buoyant or small and dense. The large buoyant LDL is actually considered a type of good LDL because it is the LDL that transports fatty acids and cholesterol to tissues so that you can make new cells in each of your organs, or so that you can repair damaged cells. It is the small dense LDL particles that tend to be dangerous.

To understand why, you have to know a little bit about a protein in LDL particles known as apolipoprotein B protein, or ApoB for short. ApoB is a ligand for the LDL receptor. These LDL receptors are found on nucleated cells And this ApoB protein found in LDL particles facilitates the particles being endocytosed by the cell. So if ApoB can interact with a cell's LDL receptor, then that particle can be brought into the cell and properly utilized. This uptake of the LDL particles is primarily done by the liver, which removes around 70% of LDL from the circulation. But again, other cells do it too. The problem is smaller LDL particles are not necessarily easily endocytosed.

When the particles are smaller, the receptor recognition site, which is the region of this ApoB protein, is partially obscured. The real-world consequences of this are that small, dense LDL particles get to circulate longer than larger buoyant variety. By staying around in the circulatory system longer, the particle is able to undergo transformations as a consequence of oxidative stress and inflammatory processes. And this is ultimately the beginning of the formation of a plaque in the artery. So when we refer back to our randomized controlled trial earlier that we mentioned, when we talked about how refined sugar led to an increase in both small dense LDL particles and an increase in inflammation, it should now be quite a bit more clear why this is really a recipe for disaster.

We can increase our large buoyant LDL by increasing our consumption of saturated fat. That's step one. But this by itself, the randomized controlled trials seem to suggest, is not enough. We need to then convert that large buoyant LDL into small dense LDL, most likely by consuming refined sugars. And in doing so, also increasing our systemic inflammation. Now, at this point, we've created a state known as atherogenic dyslipidemia. This is the pattern most strongly associated with heart disease and is characterized by elevated levels of triglycerides and small dense LDL particles. And low levels of the large buoyant HDL cholesterol.

So, hey, wouldn't it be nice if you could just walk into your doctor's office and find out what LDL particle size is predominantly floating around in your arteries? Well, you can if you ask for it. Unfortunately, these more advanced tests to measure the particle size of LDL and even HDL, which also comes in different particle sizes, have not made it into the standard of care and really aren't even usually part of the dialogue. But it could be, and it should be, and it's something that you can ask your doctor for. It's readily available from Quest Diagnostics as well as other places and is known as the ion mobility test.

You can learn more about the importance of particle size and the effects of atherogenic dyslipidemia and heart disease risk by referring to my previous podcast with Dr. Ronald Krauss that's available on YouTube and also here on iTunes. This whole discussion of saturated fat and heart disease, however, isn't quite done. It would be nice if we could simply say it's dietary intake of refined sugar and leave it at that. But the reality is the way our bodies respond to food is also complicated by genetics. This area is a source of endless fascination for me, and it's one reason why we're unlikely to find the one true diet to rule them all. Throughout human history, diet has been dictated according to geography.

When you live in a certain part of the pre-industrialized world, You will only have certain foods available to you, and the foods that you have available to you will have different compositions. They will have different macronutrients. They will have different micronutrients. Some populations may have eaten more animal products, some less. Within a given region, it is reasonable to expect that over time, people would, over generations, adapt to being able to tolerate very different nutrient thresholds and indeed to even be more well-suited for their particular dietary niches. So where your ancestors spent their time may have a lot to do with how your body responds to certain foods. That's the theory anyway.

Regardless of how our little gene-nutrient idiosyncrasies came to be, it doesn't change the fact that they exist. These variations in our genes that make them operate a little differently from similar versions in other members of the human population are known as genetic polymorphisms. We'll talk about specific genetic polymorphisms that play into this whole saturated fat thing and how you can learn more about your polymorphism specifically. But first, I want to talk about how weighty this issue of individual variation is. One of the best examples that I have seen yet demonstrating the immense variability in how people respond to the same foods was a publication that came out in 2015 in the Journal of Cell entitled Personalized Nutrition by Prediction of Glycemic Responses.

The study looked at the blood glucose responses of over 800 different people to various foods, including fat and also carbohydrates. which were sourced from both refined sources as well as whole foods with fiber. And what the study found is that the blood glucose response varied from person to person based on their genetics, their microbiome, and other lifestyle factors like sleep and exercise. And not just by a little bit. Some people had a very high glucose response when eating carbohydrates, while others not so much. Dietary fat had a low glucose response, but in some people it caused a high glucose response.

Across the board though, fiber consumption seemed to predict a long-term benefit for the glucose response, Which would make sense since it would affect the type of gut bacteria and gut bacteria also have an impact on controlling the glucose response. The variability of the glucose response shown in this study on the whole undermined the entire concept of a glycemic index, which refers to the elevation of blood glucose following ingestion of a carbohydrate. Because these 800 different individuals had such varying glucose responses to different carbohydrates, and the response was so specific to their own unique microbiome, genetics, and other lifestyle factors.

Like exercise, that it had much less to do with the glycemic index number and a whole lot more to do with the constellation of things going on in their bodies and lives. Now, I don't mean this podcast to be a glycemic index killer. In fact, glycemic index may still be a useful general rule of thumb. However, results like these do tell us that we probably need to account for more factors. Instead of talking about all the various tips and tricks I have for diet and lifestyle that are broadly applicable, I want to now take a moment to talk about the genes involved in this whole saturated fat story.

When talking about genetic polymorphisms, putting aside the realm of epigenetics for just a moment, we're largely talking about dealing with and navigating around the hand we were dealt with at birth, striving to understand rather than ignore the existence of. While refined sugar makes for a nice scapegoat for these observational studies linking saturated fat perhaps more directly to heart disease than it should be, I believe that genes play a significant enough role that population biasing may be a part of this problem of observational studies blatantly contradicting each other. Right at the top of the list of this potential culprits is the FTO gene, which encodes for a protein literally known as the fat mass and obesity-associated protein.

Some polymorphisms in this gene can increase obesity risk by up to 2.76-fold, particularly in the context of a high saturated fat and low polyunsaturated fat intake. Most notable among the polyunsaturated fats are the omega-3 fatty acids, but they also include a number of other fats. Good whole food sources of polyunsaturated fats include foods like fatty fish, such as salmon, herring, as well as nuts. Other polymorphisms in this gene have shown that saturated fat may have a negative effect on blood glucose and insulin levels and increases type 2 diabetes risk in individuals. Individuals that are at a high risk of obesity due to FTO polymorphisms may particularly benefit by having a higher polyunsaturated fat intake and a lower saturated fat intake.

The next potential culprits responsible for variation in how individuals respond to saturated fats are a group of nuclear receptor proteins That function as transcription factors regulating the expression of genes involved in cellular differentiation, development, tumorigenesis, and more relevant to this conversation, metabolism of carbohydrates, lipids, and proteins. These proteins are known as peroxisome proliferator-activated receptors, which are sort of a mouthful. So we'll just call them PPARs for short. The 2 genes that are especially relevant to this discussion are PPAR alpha and PPAR gamma.

PPAR-alpha is primarily activated through the binding of polyunsaturated fatty acids and is richly found in brown adipose tissue, the liver, and to a lesser extent in the kidney, skeletal muscle, heart, small and large intestines. PPAR-alpha also plays a very important role in the process of ketogenesis— ketone bodies that are produced from the oxidation of fat, which normally occurs during carbohydrate restriction or fasting. Activation of PPAR-alpha promotes the uptake utilization, and catabolism of fatty acids by activating genes involved in fatty acid transport, fatty acid binding and activation, and fatty acid oxidation.

There is a polymorphism in this gene that has been associated with lower PPAR-alpha activity and a twofold higher risk of type 2 diabetes, increased levels of triglycerides, increased total cholesterol, increased LDL cholesterol, and especially important, increased small dense LDL particles in the context of high saturated fat intake. And low polyunsaturated fat intake. Since this gene is activated by polyunsaturated fatty acids and plays a major role in lipid metabolism, including fat oxidation, a ketogenic diet that is high in saturated fat and low in polyunsaturated fats may be less advisable for people at risk for atherogenic dyslipidemia due to this particular polymorphism, where it may be more important to be mindful of having a majority of dietary fat intake slanted more towards higher polyunsaturated fat and less saturated fat.

In a continuation of the peroxisome proliferator-activated receptor gene, we'll shift away from talking about PPR alpha to talking about PPR gamma. PPR gamma is a master regulator of fatty acid storage and glucose metabolism. The genes activated by PPR gamma stimulate lipid uptake by fat cells, as well as adipogenesis, which is the creation of new adipocytes or fat cells. PPR gamma increases insulin sensitivity in muscle tissue and increases gluconeogenesis in the liver, which is the creation of glucose from non-carbohydrate sources, including lipids. We find PPAR gamma mostly activated in adipose tissue, colon, and immune cells called macrophages.

People with certain polymorphisms in this gene that also have a lower intake of polyunsaturated as well as monounsaturated fat intake, but have a high saturated fat intake, have a higher type 2 diabetes risk and higher obesity risk. But when there is a higher monounsaturated and polyunsaturated fat intake and a lower saturated fat intake, Their obesity and type 2 diabetes risks are normal. Polyunsaturated fatty acids activate the PPAR gamma gene. Since I haven't mentioned monounsaturated fats up until this point, these fats are found from sources like avocados, olive oil, and olives. And last but certainly not least are the polymorphisms in the apolipoprotein E gene, also known as APOE as in Edward, not to be confused with APOB as in boy. Of which there are 4 different versions of.

I'm not going to go into great detail on ApoE because that could be an entire podcast on its own. But I will briefly mention that one particular common version of this gene referred to as ApoE4. ApoE4 is associated with LDL cholesterol not being recycled by the liver very well. As a consequence, higher concentrations of LDL particles are in the circulatory system for a longer period of time, Which then have a higher chance of undergoing inflammatory transformations and forming small, dense LDL particles and/or oxidized LDL. It's probably wise for people with APOE4 to moderate their saturated fat intake. Okay. So how do you find out if you have any of this stuff? If you want to learn more about whether you have any of these specific gene polymorphisms, you have a few options.

The first is that you probably need to go out and pick up a genetic test from a company like 23andMe, with whatever their minimum package is that still gives you access to your raw data. You don't need their health reports, just the raw data from the test results. I believe this is included with even their most minimal package. The next thing you need to do is run that raw data through one of the variety of third-party reports out there. One I recommend a lot is Promethease. That's P-R-O-M-E-T-H-E-A-S-E. This is a great website that will run your data against thousands and thousands of single nucleotide polymorphisms and provides you with a searchable copy of the results. The problem with Promethease is also its biggest advantage. They give you everything and the kitchen sink.

It's absolutely like drinking from a fire hose. Some of it is very interesting, but a lot of it will also bore you to tears. Still, I recommend checking it out. You can find that at promethease.com. However, if you'd like curation of interesting genetic information that focuses more on polymorphisms that might lead to Actionable information, I recommend checking out the genetic tool on my website. You can find that at foundmyfitness.com/genetics. Once again, that's foundmyfitness.com/genetics. This tool will also readily tell you about your FTO, PPAR gamma, PPAR alpha polymorphisms. So definitely check that out. Okay, back to saturated fat story. There were 2 major, major negative repercussions to the guidelines that encouraged people to reduce their saturated fat intake.

First, people increased their intake of refined carbohydrates and processed foods. But perhaps the more destructive consequence was the appearance of hydrogenated oils or trans fats like margarine. These are deadly, quite literally. They significantly increase the risk of heart disease in small amounts. The problem is these trans fats get incorporated into your cells. Probably even more important than using fatty acids to produce energy is the fact that they, in addition to cholesterol, are required to make new cells. That is kind of important. Every time you make a new immune cell or a new liver cell or a new brain cell, you need fatty acids and cholesterol because they make up the membrane that encapsulates all the cellular contents inside a cell.

Well, trans fats have very different physical properties than fatty acids found in nature. When they get incorporated into the cell, they are very rigid, and so they make the cell really stiff. When this happens in endothelial cells that line the arteries, it causes the arteries to stiffen. And this increases heart disease risk. In 2015, the FDA mandated that trans fats be pulled off all the shelves and pulled out of all foods in the US, but food companies were given 3 years to get them off the shelves. So we still have some time before it's out of circulation, at least around here. The second negative repercussion to the guidelines that encourage people to reduce their saturated fat intake is that resulted in people consuming more refined foods that were high in refined sugar.

because they were fat-free foods. From our discussion earlier, we already know where that leads. In most people, it would lead to an increase in small dense LDL and indeed inflammation, which is a great path to heart disease. But to sort of riff on this link a little bit more for a minute, increased consumption of high fructose corn syrup and sucrose has also been linked to a 35% greater risk of heart attack and fatal heart disease for those consuming the equivalent to 1 to 2 servings per day of sugar-sweetened beverages. Another study including over 400,000 people found that those with the highest intake of refined sugar had a fourfold increase in heart attacks compared to those with the lowest intakes. I could go on and on about refined sugar beyond this heart disease stuff.

I could tell you about the effect of refined sugar consumption on risk of cancer and an oncogene known as beta-catenin, how refined sugar increases dopamine and reward pathways in the brain in a manner that is not too unlike drugs of abuse like cocaine, tobacco, and morphine, and why this makes quitting sugar cold turkey very challenging for some people. How the consumption of refined sugar can change the structure of neurons in the brain. How stopping the consumption of refined sugar actually takes normal food and makes it taste sweeter by itself over time. How having high blood sugar, even in the range of prediabetes, is actually associated with brain atrophy in the hippocampus and amygdala.

How higher consumption of high fructose corn syrup was shown to impair the brain's ability to repair itself in rat studies. How a whopping 10% of adults get 25% of their daily calories from added sugar, and over 70% of adults get at least 10% of their calories from added sugar. How healthy adults between the ages of 20 and 65 that drink 12 fluid ounces of soda per day had much shorter telomeres in their white blood cells, a marker of biological aging, than people the same age that didn't drink sodas, and how this was sometimes equivalent to literally years of extra biological age. But instead of doing that, I'll save it for another podcast. Thank you for listening today.

Hopefully many of you found it an interesting exploration on the link between saturated fat consumption and heart disease. To sort of get to the bottom line, there's probably good reasons why the link breaks down. But when talking about the individual, there probably really are people that depending on their genetics should at least moderate the saturated fat consumption and indeed boost their consumption of polyunsaturated and monounsaturated And all of us should do everything that we can to avoid refined sugar. That stuff is a mess, and removing it is one of the best big dietary changes each of us can make if we're coming into this healthier living thing cold turkey and trying to make some big improvements quickly.

Not to mention, it seems to be a very, very important plausible missing link when it comes to this whole saturated fat-heart disease connection. One thing that I also didn't get into in this podcast, but I will get into in a future one more focused on sugar, Is that fructose from fruit is very different than consuming added high fructose corn syrup for a variety of reasons. Yes, it may block ketosis if that's your thing, but on no level is consumption of whole fruit to be considered vice in and of itself. Mic drop. Okay. A few quick reminders. If you're interested in the genetics angle that this podcast got into and already have 23andMe data, you can head over to foundmyfitness.com/genetics and run your report. That's foundmyfitness.com/genetics.

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