By "Fooling" The Body, Molecule Helps Set Course To Heart Disease

The study is the first to link this enzyme molecule to high cholesterol levels and hardening of the arteries, also known as atherosclerosis, and suggests that the molecule's action may be happening in many cases of heart disease and stroke, currently the leading killer of Americans. The researchers' findings appear in the online version of the American Journal of Physiology - Endocrinology and Metabolism.

Dr. Nick Vaziri, professor of medicine and physiology and chief of nephrology at UCI Medical Center, and his colleagues found an enzyme called ACAT-2 in very high levels in rats with simulated kidney failure. By "fooling" the liver into operating as if cholesterol levels were low, ACAT-2 accelerated the production of fat molecules known as VLDL, or "bad cholesterol," which lead to the buildup of atherosclerotic plaque and, subsequently, cardiovascular disease.

Vaziri and his colleagues found that ACAT-2, which normally takes cholesterol and stores it in specialized liver cells, was much more active in cases of kidney failure. Removing the cholesterol induced the liver to sense, falsely, that cholesterol counts were too low and produce high levels of heart disease-causing lipids. In rats that had normally functioning kidneys, ACAT-2 levels were normal, as were their cholesterol and lipid levels.

"In kidney failure, which is one major cause of heart disease, we see very high levels of VLDL and other lipid abnormalities that lead to the production of atherosclerotic plaque," Vaziri said. "We discovered that high levels of ACAT-2 in kidney failure accelerated the transport and storage of cholesterol into cells in the liver, which induced the liver to increase production of VLDL and other lipids as the liver sensed an apparent--but false--low level of cholesterol. It's possible that this activation of ACAT-2 may also be happening in the development of cardiovascular cases that are not due to kidney failure."

ACAT also helped directly in the buildup of plaque associated with arteriosclerosis, the researchers found. As ACAT-2 acted to store circulating cholesterol, it created bodies called foam cells, which are the building blocks of atherosclerotic plaque. As foam cells accumulate, the atherosclerosis progresses, leading to artery blockage and the blood flow reduction seen in heart disease. Plaque also can break off and potentially lead to stroke.

Heart disease is the leading killer of Americans, resulting in about 40 percent of all deaths every year; about 62 million have some type of cardiovascular disease, according to the American Heart Association. A leading cause is atherosclerosis. Kidney failure is another important contributor to the high rates of heart disease. About 20 million Americans are suspected of having some degree of kidney failure.

While ACAT-2 is found in the liver, its close relative, ACAT-1, is an enzyme found in most other organs and tissues in the body. Vaziri and his team are looking at whether inhibitors of ACAT-1 and ACAT-2 could help reduce the buildup of atherosclerotic plaque in the body.

"While our experiments were looking at kidney failure, we think that controlling ACAT production may be useful in combating atherosclerosis, regardless of its cause," Vaziri said. "Of course, researchers will have to determine ACAT levels in other disorders that lead to atherosclerosis."

Vaziri and his team, who have spent decades studying the complex interplay between kidneys, blood vessels and the heart in cardiovascular disease, are now looking at possible inhibitors of ACAT. These inhibitors, if they work, would possibly be candidates for drugs that inhibit the production of plaque that leads to disease.

Vaziri's work was supported by gifts from Thomas Yuen, chairman of SRS Labs in Santa Ana, Calif.