Acyl-coenzyme Axholesterol acyltransferase (ACAT) is a membrane-bound enzyme present in a variety of tissues and cells. Using long-chain fatty acyl-coenzyme A and cholesterol as its substrates, ACAT catalyzes the biosynthesis of cholesteryl esters, which comprise part of the neutral lipid cargo packaged into the cores of very low-density lipoproteins and chylomicrons. Under pathophysiological conditions, in cholesterol-loaded macrophages, ACAT converts excess cholesterol into cholesteryl esters. This action reduces the amount of cholesterol available for efflux and converts the macrophages to foam cells, which are the hallmark of early lesions of atherosclerosis. In mammals, two Acat genes exist that encode for two similar but different proteins, ACAT1 and ACAT2. Both enzymes are potential drug targets for pharmaceutical intervention against diseases including atherosclerosis and hyperlipidemia. Recent evidence suggests that ACAT may also be a potential drug target for treating Alzheimer's disease (AD). The long-term objective of this research is to understand the functions of ACAT in vitro, in intact cells, and in animals. For the current proposal, there are two specific aims.
The first aim i s to test certain key features of a biochemical model proposed to explain ACAT1 as an allosteric enzyme.
The second aim i s to determine the pathophysiological role of ACAT in a mouse model for AD. The outcome of the first specific aim will provide the first biochemical model for ACAT;this model will help increase our understanding of the mechanisms of actions of ACAT inhibitors. The outcome of the second specific aim will help determine the pathophysiological role of ACAT in a major neurodegenerative disease. This project aims to build a biochemical model for ACAT1, an enzyme critical to cholesterol metabolism, transport, and storage. Knowledge of how ACAT behaves and is inhibited, as well as what role it may play in the development of Alzheimer's disease in a mouse model, can improve our understanding of the causes and prevention of Alzheimer's disease, a progressive brain disorder that affects an estimated 4.5 million Americans and is becoming increasingly common in the U.S. population.
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