Lipoproteins transport lipids through the circulatory system and lipoprotein receptors mediate the targeted delivery of these lipids to cells. Abnormalities in lipoprotein and/or lipoprotein receptor metabolism are directly associated with the pathogenesis of atherosclerosis and other diseases. The long range goals are to understand in molecular detail the cellular processes which underlie lipoprotein metabolism and atherosclerotic disease and to use this understanding to help develop rational approaches for the diagnosis, treatment and prevention of atherosclerotic disease and to use this understanding to help develop rational approaches for the diagnosis, treatment and prevention of atherosclerosis. Specific goals include 1) characterization of the properties and functions of newly discovered lipoprotein scavenger receptors, 2) use of somatic cell and molecular genetics methods to identify the gene products and functions required for lipoprotein receptor function, and 3) training of outstanding young research investigators. We have identified three distinct classes of lipoprotein scavenger receptors, SR-A, SR-B and SR-C. Unexpectedly, SR-B (type I, SR-BI) is the first """"""""new"""""""" native LDL receptor to be identified since Brown and Goldstein discovered the classic LDL receptor 20 years ago. unlike the classic LDL receptor (LDLR), SR-BI is expressed primarily, but not exclusively, in adipose tissue. SR-BI may play an important role in normal lipoprotein and lipid metabolism and possibly contribute to the molecular mechanisms underlying atherosclerosis and obesity. The molecular biology and physiological function(s) of this receptor in vitro and in vivo will be examined in detail. The molecular basis for LDL recognition and its cell type and tissue specific expression will be determined, as will its intracellular location and its functions. Experimental methods will include the generation of transgenic and knockout models. We have begun the characterization of LDL receptor-deficient Chinese hamster ovary (CHO) cell mutants which define 2 genetic complementation groups: ldlB and Id1C. Defects in the genes defined by these mutants interfere with the intracellular processing and stability of LDL receptors by preventing normal postranslational processing in the Golgi apparatus. The LDLC gene encodes ldlCp, a novel peripheral Golgi protein whose attachment to the cytoplasmic surface of the Golgi requires the function of the LDLB gene. The mechanisms by which these genes function to permit normal LDL receptor activity will be explored using a variety of molecular genetic (e.g., cloning), biochemical and immunochemical methods. This should provide insights into the mechanisms responsible both for normal endocytic recycling and turnover of LDL receptors and other glycosylated lipoprotein receptors.
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