In a recent study, researchers determined that derivatives of natural emulsifiers such as phospholipids found in high-fat and high-cholesterol diets can promote hardening of the arteries via the interaction of gut bacteria with the immune system. This study could pave the way for targeted interventions for individuals at high risk of heart disease.
Obesity and a diet high in cholesterol and fat are well-established risk factors for atherosclerosis. In fact, people who are obese are two and a half times more likely to develop heart disease. However, a mechanistic link between obesity and atherosclerosis eludes scientists. The researchers behind this new study believe the link may be in how certain derivatives of the natural emulsifiers in a Western diet change the way the cells that line the gut interact with the bacteria in the gut. The team published their findings in the journal Lipid Research.
“The gut is the diet’s window into the body,” said Srinivasa Reddy, UCLA professor of medicine and corresponding author on the study.
atherosclerosis, sometimes calledArteriosclerosisPlaque builds up in blood vessels and can interfere with blood flow to vital organs, which can lead to a heart attack or stroke. These plaques are composed of cholesterol, phospholipids, and other lipids; and immune cells and fibrous components.
We study the natural emulsifiers in the diet called phospholipids. For example, if you look at salad dressing and shake it up, it’s the phospholipids, or emulsifiers, that keep the oil in the globules. These emulsifiers can be modified by specific enzymes in the gut cells into very potent pro-inflammatory molecules in the body.”
Alan Fogelman, UCLA professor of medicine and project supervisor
To examine the complex relationship between diet and atherosclerosis, the researchers used a mouse model that not only has high levels of low-density lipoprotein, or “bad cholesterol,” seen in patients with atherosclerosis, but also lacks the specific enzyme involved in the generation of pro-inflammatory derivatives of Natural emulsifiers in intestinal lining cells. Using this model, the researchers found that on a high-fat, high-cholesterol diet, cells that line the small intestine produce reactive phospholipids that make the gut lining more vulnerable to invasion by bacteria that live in the gut.
“The natural defenses of gut lining cells to keep bacteria in the lumen of the intestine decrease when you take in high amounts of cholesterol and fat,” Fogelman said. “This also results in bacteria being able to directly contact cells lining your gut called enterocytes. Without these defenses, more bacterial products, such as bacterial cell membranes containing a toxic substance called endotoxin, enter your bloodstream to cause a flare-up.”
The release of bacterial products from the gut into the bloodstream sets off an alarm in the immune system, which deploys immune cells into the blood to eliminate the potential threat.
“Obese people and people who eat diets high in fat and cholesterol have higher levels of endotoxins in their blood,” Fogelman said. “It’s not at the level of causing sepsis, but it does cause a lower level of inflammation. And when cholesterol and fat come into the mix, the endotoxin kind of heats up the inflammation which accelerates hardening of the arteries and leads to increased heart attacks and strokes.”
The team is looking for ways to reduce phospholipid derivatives that cause endotoxins to enter the bloodstream. One method they’ve previously explored is to use mimics of high-density lipoprotein, which is sometimes called “good cholesterol.”
“We created genetically modified tomatoes in our lab that mimic good cholesterol and high-density lipoprotein,” said Arnab Chattopadhyay, UCLA project scientist and lead author of the study. “These tomatoes, when added to a diet high in fat and cholesterol, help lower cholesterol and triglycerides and also reduce inflammatory derivatives of phospholipids.”
The team said this method of lowering cholesterol and triglyceride levels may be beneficial for obese individuals who are at risk of developing inflammatory diseases such as atherosclerosis, arthritis, lupus, multiple sclerosis, and more.
Chattopadhyay, A.; et al. (2023). Role of enterocyte Enpp2 and autotaxin in the regulation of lipopolysaccharide levels, systemic inflammation, and atherosclerosis. Journal of Lipid Research. doi.org/10.1016/j.jlr.2023.100370.