Our laboratory has been engaged in basic and translational research in cholesterol homeostasis. Our goals are to understand cholesterol homeostasis in the CNS and in systemic tissues and to use the knowledge gained as the basis to develop novel therapeutic agents to ameliorate human diseases. We use biochemistry, cell and molecular biology, nanotechnology, medicinal chemistry, as well as mouse models as research tools to pursue our goal.
Cholesterol is a lipid molecule. It is present in the membranes of all mammalian cells. Cells contain different membranes. Each membrane contains certain cholesterol-rich microdomains. These microdomains are associated with specific other lipids as well as specific protein molecules. Proper distributions of these cholesterol-rich microdomains in membranes are required to provide optimal cell growth and maintenance. In many neurodegenerative diseases and in cardiovascular diseases, the individual toxins that cause the specific diseases often disrupt the cholesterol-rich microdomains and cause these microdomains to malfunction.
A favorite research subject in our laboratory is acyl-coenzyme A: cholesterol acyltransferase (ACAT), also named as sterol O-acyltransferase (SOAT). ACAT is an integral 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, but it cannot substitute the function of cholesterol in membranes. The first gene encoding the enzyme, designated as ACAT1 was identified in our laboratory through an expression cloning approach. We have also purified this protein to homogeneity and characterized it biochemically. ACAT1 is present in many cell types and plays a key role in the cholesterol storage process. In many neurodegenerative diseases, the cholesterol-rich microdomains in various cell types are disrupted. We have shown by a genetic approach that, in mouse models for Alzheimers disease and for Niemann Pick type C disease, blocking cholesterol storage by inactivating ACAT1 can divert the cholesterol storage pool, such that the mobilized cholesterol can repair the disrupted cholesterol-rich microdomains present in the cells. Based on these results, future investigations are directed to develop novel, brain-permeable ACAT inhibitors to ameliorate Alzheimer's disease, Niemann-Pick type C disease, as well as atherosclerosis. We will also use biochemical and biophysical approaches to identify the active sites and regulatory sites in ACAT1. In addition, we will investigate the consequences of inhibiting ACAT in different tissues and cells, including macrophages, neurons, microglial cells, and astrocytes, at the cell and molecular biological level.