Max Petersen, M.D., Ph.D.

ABSTRACT

This study investigates the mechanisms behind ketogenic diet-induced hypercholesterolemia (KDHC) in lean adults. It tests whether elevated LDL-c results from increased synthesis or absorption. Using deuterated water and serum markers, the project compares cholesterol metabolism in KDHC responders and non-responders. Findings will inform safer KD implementation and cardiovascular risk management.

Lay Summary:

Cholesterol plaque in the arteries is a leading cause of heart disease and death worldwide. Very high cholesterol levels cause plaque and heart disease early in life and are often due to genetic differences. However, genetic differences are not the only possible cause of very high cholesterol levels. A ketogenic diet can also cause very high cholesterol levels. This is problematic because very high cholesterol levels increase the risk of heart disease. Not everybody is susceptible to the cholesterol-raising effect of ketogenic diets. The cholesterol-raising effect happens more often in healthy, lean adults. The reason it happens is not known.

Our research aims to understand why a ketogenic diet can raise cholesterol so much and why some people are susceptible to this problem. Understanding this process could help treat people who have this condition and could help us understand which people might tolerate ketogenic diet therapies used for other diseases. It could also teach us fundamental new things about how cholesterol metabolism works in people. Cholesterol travels through the bloodstream in particles called lipoproteins. Some of the cholesterol in these lipoproteins is produced in the liver. The other main source of cholesterol in lipoproteins is the food we eat, because animal products contain cholesterol and our gut absorbs some of it. For this reason, we will study how cholesterol is produced and absorbed in the body. Our goal is to learn how cholesterol production and absorption are affected in people who have very high cholesterol because of a ketogenic diet.

One possibility is that a ketogenic diet causes too much cholesterol to be made in the liver. This is plausible because the liver can convert the ketones made on a ketogenic diet to cholesterol molecules. Another possibility is that the people who are susceptible to high cholesterol on a ketogenic diet absorb more cholesterol from the diet than the typical person. We will study healthy adults with a normal weight to explore these options because they are more likely to have high cholesterol on a ketogenic diet. We will measure cholesterol absorption in all participants and compare absorption in “Responders” who experience high cholesterol on the ketogenic diet to “Nonresponders” who do not. If high cholesterol production is the cause of high blood cholesterol on a ketogenic diet, we expect to see higher cholesterol production in these Responders during the ketogenic diet period than during the normal diet period. By learning how the ketogenic diet causes high cholesterol, doctors and patients can have better discussions about diet and heart health. This research could help improve dietary guidelines to treat high cholesterol and prevent heart disease. Finally, this research will help us learn how cholesterol metabolism responds to changes in the diet.