UC San Diego

Heparan sulfate proteoglycans mediate multiple aspects of triglyceride-rich lipoprotein metabolism through non- covalent interactions with several lipases and apolipoproteins. In the circulation, lipoprotein lipase bound to the luminal side of the microvascular endothelium catalyzes the lipolysis of triglyceride-rich lipoproteins, resulting in lipoprotein remnants. In the liver, remnant lipoproteins are cleared from the circulation by three major endocytic clearance receptors, including the heparan sulfate proteoglycan syndecan-1. This dissertation describes the identification of the lipoprotein ligands responsible for heparan sulfate mediated clearance and studies suggesting a role for endothelial heparan sulfate proteoglycans in lipolysis. Chapter 1 provides background information on the structure and function of heparan sulfate, its putative role in lipolysis, and its participation in the clearance of triglyceride-rich lipoprotein remnants. The protein components of triglyceride-rich lipoproteins that bind to heparan sulfate are described. Chapter 2 provides evidence that led to the identification of the physiologic proteins responsible for lipoprotein binding to hepatic heparan sulfate proteoglycans. Chapter 3 describes studies of several mutant cell lines and mice that suggest a role for endothelial heparan sulfate proteoglycans in lipolysis. Chapter 4 presents on-going and future studies and the relevance of these findings to human disease