A High Fat Diet Accelerates Atherosclerosis Less Directly than One Might Suspect
High blood cholesterol accelerates the onset of atherosclerosis, making it easier to reach the tipping point at which localized excesses of cholesterol form in blood vessel walls. The majority of cholesterol is generated in the liver, not obtained from the diet - and yet high fat diets are well proven to accelerate atherosclerosis. Researchers here provide evidence for the mechanism to be less direct than might be expected, involving the gut microbiome and its relationship with tissues and the immune system. Certain components of dietary fat lead to a cascade of events that provoke an inflammatory response, and the more fat, the greater the chronic inflammation.
Anything that induces a lasting state of unresolved inflammatory signaling will accelerate the development of atherosclerosis. This is again a matter of shifting the tipping point at which the innate immune cells called macrophages, responsible for clearing excess cholesterol from blood vessel walls, become overwhelmed by circumstances. Inflammatory signaling shifts macrophages into a state more appropriate for defense against pathogens than for clearing up metabolic debris. Fewer macrophages clearing cholesterol means a greater deposition of cholesterol.
High-fat diet 'turns up the thermostat' on atherosclerosis
Obesity and a high-cholesterol, high-fat diet are both well-established risk factors for atherosclerosis. In fact, obese individuals are two and a half times more likely to develop heart disease. However, the mechanistic link between obesity and atherosclerosis eludes scientists. The researchers behind this new study believe the link may be in how specific derivatives of natural emulsifiers in a Western diet alter the way that cells that line the intestines interact with gut-resident bacteria. "We study natural emulsifiers in the diet called phospholipids. For example, if you look at salad dressing and shake it up, it is the phospholipids, or emulsifiers, that keeps the oil in globules. Those emulsifiers can get modified by specific enzymes in the intestinal cells into very potent pro-inflammatory molecules in the body."
Using a mouse model, researchers found that on a high-fat high-cholesterol diet, the cells that line the small intestine churn out reactive phospholipids that makes the intestinal lining more susceptible to invasion by the bacteria that live in the gut. "The normal defenses for intestinal lining cells to keep bacteria in the lumen of the intestine are reduced when they take up large amounts of cholesterol and fat. This also results in bacteria being able to come in direct contact with the cells lining your intestines called enterocytes. Without those defenses, this results in more bacterial products, like bacterial cell membranes that contain a toxin called endotoxin, getting into the bloodstream to cause inflammation."
"People who are obese and people eating high-fat, high-cholesterol diets have higher levels of endotoxin in their blood. It's not at the level of causing sepsis, but it causes a low level of inflammation. When the cholesterol and fat come into the mix, the endotoxin kind of turns up the thermostat on inflammation and that accelerates atherosclerosis and leads to increased heart attacks and strokes."
Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr-/- mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet. Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in intestinal mucus.
We conclude that the Western diet increases the formation of intestinal OxPL, which i) induce enterocyte autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis.
Obese individuals being 2.5x more likely to have heart disease does not prove high-fat high-cholesterol diets to be a risk for atherosclerosis. Every time I read this stuff I see research built on the hollow foundations laid by Ancel Keys. Usually this stuff is backed up, as here, by mouse studies - creatures for which fat is not a natural part of their diet but grains are.