Gene tweak cuts fat-heart disease link in mice

A new study in mice raises a tantalizing possibility – that humans may one day be able to eat any kind of fat they want without raising their risk of heart disease.

"We deleted an enzyme in mice and they could eat any type of fat and not get heart disease," said Lawrence Rudel, Ph.D., a professor of comparative medicine. "If you’re a mouse, it’s great. Of course, we don’t know yet if it will be the same in humans."

Rudel’s findings are reported online by Arteriosclerosis, Thrombosis and Vascular Biology and will appear in a future print issue.

The study involved deleting a gene in the mice that causes production of ACAT2, an enzyme that alters the molecular structure of cholesterol so that it can be transported to the body’s cells.

"Regardless of the type of fatty acid in the diet, even trans fat, no atherosclerosis occurs if the ACAT2 enzyme isn’t present," said Rudel. "Our research in animals tells us that ACAT2 is a potential treatment target to protect people against heart disease."

Groups of female mice with and without the ACAT2 gene were fed six different diets enriched with one of these types of fat: fish oil, flax seed oil, polyunsaturated fat from vegetable oil, saturated fat, trans-monounsaturated fat and cis-monounsaturated fat, such as in olive oil.

Fish oil, flax seed oil and polyunsaturated fats are considered "healthy" fats. Saturated fat – found in meats, milk and cheeses, coconut oil, palm oil and palm kernel oil – is considered a main cause of high cholesterol.

There are two types of monounsaturated fatty acids, "cis" and "trans," which are named according to their shapes. Trans-fatty acids are formed when vegetable oil is treated to make it less likely to go rancid and are found in many fried foods, baked goods and potato chips. Cis monounsaturated fat is naturally occurring and is particularly high in canola and olive oil. Recently, the U.S. Food and Drug Administration has required that levels of trans-fats be listed on food labels.

After 20 weeks on the diets, the mice that had the active ACAT2 enzyme and were fed saturated fat and both types of monounsaturated fat had higher levels of cholesterol and more atherosclerosis than the mice that were fed polyunsaturated fats. All of the mice without the ACAT2 enzyme were protected against atherosclerosis, which is the buildup of fatty deposits in the blood vessels that can lead to heart attacks and strokes.

"Regardless of the diet fed, the mice without ACAT2 were protected from atherosclerosis," said Rudel.

Eliminating ACAT2 did not interfere with the normal processing of cholesterol. ACAT2 is one of three enzymes that can change cholesterol into a form that can be more easily carried in blood. Studies in both mice and monkeys show that when cholesterol is altered by ACAT2, it is more likely to build up in blood vessel walls and cause atherosclerosis.

Rudel hopes to get funding to repeat the study in monkeys.

"If it works in monkeys, it would be proof of concept that it could work in humans," he said.

He also hopes the research will lead to a drug that can inhibit the enzyme’s actions in humans. Currently, there is a compound that can block ACAT2, but it must be injected so isn’t quite as practical as a drug. He is collaborating with a pharmaceutical company that is working to find a compound that could be taken orally.

Scientists already know that humans produce ACAT2 in the liver and that women have lower levels than men. Research has shown that estrogen can lower ACAT2 production, which may partly explain why women are less likely than men to get heart disease during their estrogen-producing years.

"All of these findings tell us that a potential treatment for protecting against heart disease is a compound that decreases ACAT2 activity," said Rudel.

Wake Forest University Baptist Medical Center

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May 7, 2007