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P&S Journal

P&S Journal: Fall 1997, Vol.17, No.3
Research Reports
Cholesterol Esterification

Columbia researchers have identified genes that code for an enzyme that metabolizes cholesterol in cells and have applied for a patent on a screening test for compounds that selectively inhibit the enzyme. The findings could lead to the development of drugs to treat atherosclerosis, Alzheimer's disease, and a rare genetic disorder known as Niemann-Pick disease type C.

Dr. Stephen L. Sturley, assistant professor in the Institute of Human Nutrition, and colleagues identified two genes in yeast (Saccharomyces cerevisiae) that code for the enzyme ACAT (Acyl-CoA: cholesterol acyltransferase), which leads to storage of cholesterol in cells. The researchers then identified similar additional genes in humans.

The ability to control ACAT has implications for the treatment of several diseases, says Dr. Sturley. That's because ACAT allows the body to store cholesterol: It diverts cholesterol from a form found in membranes to a storage form in the cytosol. Without ACAT, cells can only store a limited amount of cholesterol. Therefore, blocking ACAT may help inhibit the development of atherosclerosis.

ACAT is also involved in Niemann-Pick type C disease, says Dr. Sturley. In this autosomal recessive disease, a genetic defect prevents cholesterol from being transported to the enzyme. As a result, cholesterol accumulates in the cells of the body to toxic levels, causing a progressive neurological disorder. Children with Niemann-Pick type C generally have a short life span. In a study led by NIH colleagues, Dr. Sturley and his lab collaborated on the recent identification of the human gene for this disorder and have shown that a counterpart to this gene also exists in yeast.

ACAT and its role in sterol transport may be involved in the onset of Alzheimer's disease. Niemann-Pick type C and Alzheimer's have several features in common: Both involve the deposition of amyloid plaques and the hyperphosphorylation of tau, says Dr. Sturley. He and his colleagues are now studying Alzheimer's disease and the role of ACAT in their yeast model.

The researchers also found that some of the human ACAT genes they identified are expressed in specific tissues. They have filed a patent application for a screening test that inhibits any one of the three ACAT enzymes. "The screening is based on the idea that you may be able to selectively inhibit the enzyme to control a specific disease," says Dr. Sturley. This opens the way for the development of drugs to control ACAT-related diseases.

Dr. Sturley's research team includes Hongyuan Yang, Zhongmin Guo, Peter Oelkers, Arthur Tinkelenberg, Ben Lewin, and Fred Alcantara. The New York City affiliate of the American Heart Association and the Ara Parseghian Medical Research Foundation (founded by the former football coach of Notre Dame, who has three grandchildren afflicted with Niemann-Pick type C) supported the research.

copyright ©, Columbia-Presbyterian Medical Center

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