Ta Yuan Chang

Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is a membrane protein located in the endoplasmic reticulum. It catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acyl-coenzyme A. Cholesteryl ester is the storage form of cholesterol. The first gene encoding the enzyme ACAT1 was identified in our laboratory. We have also purified this protein to homogeneity and characterized it biochemically. In many neurodegenerative diseases, the cholesterol-rich microdomains in the membranes of various cell types are disrupted. We have shown that in mouse models for Alzheimer's disease and for Niemann Pick type C disease, inactivating ACAT1 can divert the cholesterol storage pool, such that the "mobilized cholesterol" can repair the disrupted cholesterol-rich microdomains. Future investigations are directed to develop novel ACAT inhibitors to ameliorate Alzheimer's disease, Niemann-Pick type C disease, and atherosclerosis. We will also use biochemical and biophysical approaches to identify the active sites and regulatory sites in ACAT1 and to investigate the mechanistic consequence of inhibiting ACAT in macrophages, neurons, microglia, and astrocytes.