[Lipids, Inflammation, and Atherosclerosis mp3]
Today’s guest is the venerable Dr. Michael Rosenfeld, cardiovascular disease researcher and college professor extraordinaire. Most of his studies focus on atherosclerosis and the myriad factors that influence it.
Aside from being a pain-in-the-ass to pronounce, what exactly is atherosclerosis?
Before discussing the etiology of the disease it is important to have an understanding of how lipids are transported by the body. This is actually a more complex issue than one might suppose. Think about it: the human body is essentially an aquatic environment, and we all know that lipids are insoluble in water and will aggregate with other lipids in polar environments. So how would you be able to reliably and consistently transport dietary fat from your intestines to your liver and other organs and tissues as needed? You also need to consider that while some blood vessels are large in diameter others are quite small. Organisms like us have evolved a system to transport fats using what are called lipoproteins. They are basically tiny balls of triglycerides and cholesterol with a surface coat of various proteins and phospholipids that allow them to move about and interact in the polar environment of human plasma. There are essentially four kinds of lipoproteins: chylomicrons, very-low density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). I won’t go into great detail about all of them right now, but each contains varying amounts of triglycerides and cholesterol and have slightly different proteins on their surfaces.
What do lipoproteins have to do with atherosclerosis? I’ll tell you. LDL particles are like the hot dog vendors at baseball games. They swim around the blood saying “Hiyoooo! Who needs cholesterol?? Get your cholesterol here! Use it for all kinds of things: bile salts, vitamin D, lipids rafts, testosterone… you name it! I got some fresh hot cholesterol just for you.” If a cell needs some cholesterol then it manufactures an LDL receptor, sticks it onto the cell membrane, and grabs any available circulating LDL. The LDL particle gets endocytosed and the cell can then use the delicious, gooey cholesterol for whatever it needs.
So what’s the problem? The problem is that LDL has a tendency to migrate through the endothelial cell layer of blood vessel walls and become trapped in the intima where it becomes oxidized or modified in some way. The oxidized/modified LDL particles trigger an immune response which ultimately leads to macrophages – informally known as scavengers or sometimes even garbage collectors – coming in and engulfing the oxidized/modified LDL. Now one of two things can happen here: 1) The cholesterol from macrophages can be handed off to HDL particles. The HDL can then take up this cholesterol and transport the it back to the liver to be recycled. The HDL could also give it to other lipoproteins in the blood. This process is known as reverse cholesterol transport. Or 2) The macrophage can hang out in the intima and continue to gobble-up incoming modified/oxidized LDL particles. This will lead to the formation of foam cells.1, 2
To make a long story short one or two or five foam cells within the vessel wall is no big deal, but over time, if the conditions are right, foam cells can accumulate within the vessel walls leading to a host of things you don’t want to happen with your arteries such as: narrowing of the blood vessel, chronic inflammation, recruitment of more macrophages, rupturing foam cells leading to all the oxidized LDL spilling out all over the place, migrating smooth muscle cells into the intima to wall-off the lesion, formation of a necrotic core filled with dead cells and cholesterol, and eventually rupture of the vessel wall (called a thrombosis) when all the contents spill out and can slow or stop the flow of blood. Platelets are then mobilized to repair the damage, but this probably only exacerbates the problem. If the thrombosis occurs in a coronary artery this can be deadly.
Inside an artery with advanced atherosclerosis
So what does this have to do with nutrition? There are several risk factors for atherosclerosis that can be manipulated via the diet. The following are risk factors that are considered to be “definitely modifiable” in the scientific and medical literature:
- Blood Pressure
- Sedentary Lifestyle
The following risk factors are classified as “potentially modifiable”
- Oxidized Lipids
- Glucose Intolerance
And there are some factors you just can’t do anything about
Now one might think that levels of cholesterol in the blood are directly related to the amount of cholesterol ingested in the diet. It appears to make logical sense, right? As it turns out dietary cholesterol doesn’t have a huge effect on circulating cholesterol. Most of us only absorb roughly 50% of dietary cholesterol. Even if you do ingest quite a bit of cholesterol from your diet your cells can compensate somewhat by down-regulating things like endogenous cholesterol synthesis. There is even a remarkable case study about a farmer that ate approximately 25 eggs a day (which adds up to an enormous amount of dietary cholesterol) and still had more or less normal serum cholesterol levels. The author claims that farmer was able to maintain cholesterol homeostasis by producing a ton of bile acids (made from cholesterol) and probably excreting most of it in the stool. Bear in mind, however, that this guy was probably an outlier as many case-studies are.
Okay, if dietary cholesterol doesn’t have a huge influence on serum cholesterol, then just what the hell does? Surprisingly saturated fat intake has a much larger effect on LDL than actual cholesterol intake. What do I mean by this? Well many studies have shown that if you subsist on a diet where your main source of fat is of the saturated kind, then it is likely that your LDL levels are high, but if you switched to fats consisting of mainly mono- and polyunsaturated fatty acids then your LDL levels are likely to drop significantly. Good news, right? Sure, olive oil all around! Oh, and with the caveat that your HDL levels could also decrease. Bummer. The good news is that LDL levels will decrease much more than the HDL. And just to further complicate matters the short and medium-chain saturated fatty acids commonly found in plant-based fats like coconut oil and palm oil don’t have the effect that other saturated fatty acids do when it comes to increasing serum cholesterol. This is because short-chain fatty acids (SCFA) and medium-chain fatty acids (MCFA) are processed differently by the body; they are not packaged into lipoproteins like other fats are but instead hitch a ride on serum albumin to get to their destinations. Think of the long-chain fatty acids (LCFA) as having to get on an enormous and crowded bus to get anywhere, whereas the SCFAs and the MCFAs are small and fit and can get on a bike to go where they need. That’s kinda where the metaphor stops, though.3
What else can you do to reduce your risk of atherosclerosis? They are all in the list.
- If you’re obese you should lose weight, not just because of the reduced risk of atherosclerosis but also the substantial decreased risk in a legion of diseases, cancers, and what-have-you.
- If you’re still smoking then I assume you are well aware of the above risks but choose to ignore them.
- Get your blood pressure under control if you’re hypertensive.
- Exercise regularly or at least semi-regularly.
- Try not to get old. If you figure out how to do this let me know.
- If you have Type 2 diabetes and you can’t shake it then at least learn to manage your glucose levels.
- If you have hyperhomocysteinemia then you may have a B vitamin deficiency. Potentially an easy fix.
- There are some gene therapies being studied right now if you have a genetic disorder that causes hypercholesterolemia.
- There is also a large and growing body of evidence on phytochemicals and their antioxidant and protective effects.
- There is also a substantial amount of evidence regarding omega-3 fatty acids and their role in modulating inflammation. Take this into account please.
- If all else fails or you just want to keep eating steak and ice cream then talk to your doctor about statins.
This is all boilerplate stuff, of course. If you are reading this blog then I assume you are at least marginally interested in nutrition and already heed most of these recommendations. I didn’t get too much into inflammation in this post, but Dr. Rosenfeld and I talk about it more in the podcast. Inflammation truly deserves one or more posts on its own.
- Word on the street is that when the blokes that were first researching atherosclerosis were dissecting and examining diseased blood vessels they came upon a type of cell that looked like beer foam, and that’s how the foam cells got their name.
- It’s actually more complicated than that as you can probably imagine. It seems that if a macrophage ingests unmodified LDL then it can maintain normal cholesterol homeostasis, and get rid of the excess via reverse cholesterol transport. If the macrophage ingests a lot of oxidized LDL then it will become a foam cell.
- Wait… lemme try to extend it… So these buses sometimes get stuck on the highway and then the macrophage troll that hides underground comes and gobbles up the bus. If there are a bunch of buses then the troll will gobble those up as well and if he eats enough LDL buses then he morphs into the foam troll. Then foam troll can use his new powers of chemotaxis to silently call other trolls like a dog whistle and if enough buses and trolls show up then you have a traffic jam and everybody dies. Got it?
Astrup A, et al. (2011) The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010? Am J Clin Nutr. 93:684-688.
Breslow JN. (2006) n-3 Fatty acids and cardiovascular disease. Am J Clin Nutr. 83:1477S-1482S.
Fernandez ML and West KL. (2005) Mechanisms by which Dietary Fatty Acids Modulate Plasma Lipids. J Nutr. 135:2075–2078.
Genest J. (2003) Lipoprotein disorders and cardiovascular risk. J Inherit Metab Dis. 26:267-287.
Glass CK and Witztum JL. (2001) Atherosclerosis: The Road Ahead. Cell. 104:503–516.
Grundy, SM. (1990) Cholesterol and Atherosclerosis: Diagnosis and Treatment. New York, NY: Gower Medical Publishing.
Grundy SM. (1991) Multifactorial Etiology of Hypercholesterolemia Implications for Prevention of Coronary Heart Disease. Arterioscler Thromb Vasc Biol. 11:1619-1635.
Kern F. (1991) Normal Plasma Cholesterol in an 88-Year Old Man Who Eats 25 Eggs a Day: Mechanisms of Adaptation. NEJM. 324:896-899.
Loscalzo J (Ed.) (2005) Molecular Mechanisms of Atherosclerosis. Abingdon, Oxon: Taylor & Francis.
Nicolosi RJ, et al. (2001) Dietary Effects on Cardiovascular Disease Risk Factors: Beyond Saturated Fatty Acids and Cholesterol. J Am Coll Nutr. 20:421S-427S.
Ross R. (1999) Atherosclerosis – An Inflammatory Disease. NEJM. 340:115-126.
Siri-Tarino SW, et al. (2010) Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 91:502-509.