#033 Does Saturated Fat Cause Heart Disease?

Gut Microbiome: Diet

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.

"Welcome back, Found My Fitness 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 and how 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 over 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, were 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, 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 three 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 in 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 throughout the body, 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 control 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 You can just walk into your doctor's office and find out what 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 Krause 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 polymorphisms 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 buried from person to 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."

Ketogenic Diet Discussion

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...

"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..."

Saturated Fat Discussion

Welcome back, Found My Fitness amigos. Today we try to answer or at least explore a big question in the world of health.

"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 Thank you. getting 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 culprit says 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 higher 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 two genes that are especially relevant to this discussion are PPR-alpha and PPR-gamma. PPR-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. PPR-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 PPR 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 PPR alpha activity and a two-fold 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 dyslepidemia 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."

Saturated Fat Discussion

PPR gamma is a master regulator of fatty acid storage and glucose metabolism.

"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."