UC San Diego

Triglyceride-rich remnant lipoproteins are cleared from the circulation by hepatic receptors including the low density lipoprotein receptor (Ldlr), the Ldlr-related protein, and heparan sulfate proteoglycans (HSPGs). This dissertation describes the identification of syndecan-1 as the primary heparan sulfate proteoglycan receptor for remnant lipoproteins in the liver, characterizes its function as a receptor, and defines its relative contribution to clearance in the context of other known receptors. Chapter 1 serves as a primer on lipoprotein metabolism, provides background information about sydecan- 1 structure, function and regulation, and reviews relevant literature implicating syndecan-1 in lipoprotein clearance. Chapter 2 demonstrates the contribution of syndecan-1 to clearance in mice and in human hepatocytes, analyzes elements of syndecan-1 structure that are important for its function as an endocytic receptor, and discusses the influence of syndecan-1 in disease- associated hypertriglyceridemia. Chapter 3 introduces a new mouse model in which three hepatocyte lipoprotein receptors - Ldlr, Lrp1, and HSPGs - have been inactivated. Using this model, it is shown that HSPGs mediate clearance of triglyceride-rich lipoproteins of unique size and apolipoprotein composition. Chapter 4 reviews ongoing and future studies of syndecan-1 as a clearance receptor for triglyceride-rich lipoprotein remnants and discusses the broader implications of this work