Allen Cooper

Atherosclerotic cardiovascular disease is the most common cause of mortality in western countries. Although its pathogenesis is complex and varied the abnormal accumulation of cholesterol in intimal cells is invarient. Alterations in cholesterol metabolism alone can accelerate or slow the progression of the disease. Cholesterol homeostasis can be thought of as controlled by the interplay of intestinal and hepatic processes. The overall goal of our laboratory is to understand in molecular terms the regulation for the uptake of cholesterol carrying lipoproteins by these two organs. Current projects are:

1. Studies of the factors that govern the uptake of intestinally derived lipoproteins by the liver. Comaprison of the role of the LDL receptor and the LRP in mediating the uptake of various classes of lipoproteins and the role of of ancillary molecules in this process. Transgenic mice that over express or are defective in one or another of these pathways are being studied.

2. We are trying to create the hepatic phenotype for lipoproten uptake in non-hepatic cells by transfecting cells with proteins known to play a role in lipoprotein metabolism in the liver. In particular apo E and hepatic lipase may act as paracrine factors in directing lipoprotein uptake. These and various chimeras are being transfected into cells that can be grown both in vitro and in in vivo.

3. Regulation of lipoprotein uptake and the effects of remnant particles on the behavior of macrophages and endothelial cells is being studied.

4. Resistance to the accumulation of cholesterol as the result of dietary ingestion may be governed by the ability to catabolize the cholesterol to bile salts. The regulation of the expression of the enzyme that governs this proscess, cholesterol 7a-hydroxylase, is being studied.