Little known enzyme ACAT2 appears to be a factor in cardiovascular disease

May 2 2005

New research suggests that a little-studied enzyme ACAT2, may play a major role in cardiovascular disease because it alters the molecular structure of cholesterol.

Artery-clogging plaque, which is produced from cholesterol in our diets can cause heart attacks and strokes and drugs which target that enzyme could dramatically reduce the risk of heart disease.

Lawrence Rudel, Ph.D., professor of pathology at Wake Forest University School of Medicine, says their research in animals shows that ACAT2, a cholesterol transforming enzyme, is a potential treatment target to protect people against heart disease.

According to the American Heart Association cholesterol is made by the liver and is also found in foods such as meat, fish and dairy products and is needed to insulate nerves, make cell membranes and produce certain hormones. However, because the body makes enough cholesterol on its own, too much dietary cholesterol is associated with an increased risk of heart disease.

Rudel focussed on an enzyme that alters the molecular structure of cholesterol so that it can be transported to the body’s cells.

There are three different enzymes (ACAT1, ACAT2 and LCAT) that can change cholesterol into a form that can be more easily carried in blood.

Studies in both mice and monkeys have shown that cholesterol altered by ACAT2 is more likely to build up in blood vessel walls and cause atherosclerosis. In studies of genetically altered mice that do not produce ACAT2, levels of atherosclerosis are 85 percent lower than animals producing ACAT2. Rudel says that mice without ACAT2 do not get atherosclerosis.

Rudel and colleagues have confirmed their results in normal mice by using a molecule that blocks the effects of ACAT2, and will follow it with a pilot study in monkeys. He hopes the research will lead to a drug that can inhibit the enzyme’s production in humans, it is already known that humans produce ACAT2 and that women have lower levels than men.

Research has shown that estrogen can lower ACAT2 production, which may explain why women are less likely than men to get heart disease during their estrogen-producing years.

Rudel says that all the results show the potential for a treatment for protecting against heart disease is a compound that decreases ACAT2 activity and it may in future be considered important to test how much of patients’ cholesterol is altered by ACAT2, as well as testing levels of high-density lipoprotein ("good") and low-density lipoprotein ("bad") cholesterol.

Rudel says reducing the risk of heart disease appears to involve more than affecting the levels of good or bad cholesterol.

He is also studying how the three enzymes are activated to alter cholesterol and already evidence suggests that a diet high in mono-unsaturated fats, which include olive oil, nuts and nut butters, avocado and sesame seeds, may stimulate transformation by ACAT2.

In a study of monkeys, those that were fed a diet high in monounsaturated fat got just as much heart disease as monkeys that were fed saturated fat, even though their levels of "bad" cholesterol decreased.

The monkeys which ate monounsaturated fat had all of the positive risk factor changes, but they still got heart disease, said Rudel, and he believes it may that more of the cholesterol was transformed by ACAT2.