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New target for atherosclerosis: ACAT2

Research in animals suggests that an enzyme called ACAT2 may play a major role in the atherosclerosis, and that drugs to target it could reduce the risk of cardiovascular disease.

There are three different enzymes, ACAT1, ACAT2 and LCAT, that can change cholesterol into a form that can be more easily carried in blood.
ACAT2 ( Acyl-Coenzyme A:Cholesterol Acyltransferase 2 ), is a proatherogenic enzyme that contributes cholesteryl esters to apoB-containing lipoproteins, whereas LCAT ( Lecithin: Cholesterol Acyltransferase ) is an antiatherogenic enzyme that facilitates reverse cholesterol transport by esterifying free cholesterol on HDL particles.

Studies in both mice and monkeys showed 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.

These results have recently been confirmed in normal mice by using a molecule that blocks the effects of ACAT2.

Investigators from Wake Forest University School of Medicine hope the research will lead to a drug that can inhibit the enzyme's production in humans.

Scientists already know that humans produce ACAT2 and that women have lower levels than men.
Research has shown that estrogen can lower ACAT2 production. This could explain why women are less likely than men to get heart disease during their estrogen-producing years.

Lawrence Rudel, the lead of the research, is also studying how the three enzymes are activated to alter cholesterol.
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 LDL-cholesterol decreased.

Source: American Heart Association's Sixth Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology, 2005