Genetic analysis of proteoglycan-mediated clearance of triglycerides

Heparan sulfate proteoglycans regulate various aspects of lipoprotein metabolism through their interaction with apolipoproteins and lipases. In the liver, one or more proteoglycans facilitates the clearance of remnant triglyceride-rich lipoproteins. This dissertation describes the role of various sulfate groups on heparan sulfate necessary for lipoprotein binding and uptake, the identity of the heparan sulfate proteoglycan receptor in the hepatocytes, and the relative contribution of heparan sulfate proteoglycans and members of the low density lipoprotein family of receptors to clearance. Chapter 1 reviews literature regarding lipoprotein metabolism, hypertriglyceridemia, and relevant work implicating heparan sulfate proteoglycans in lipoprotein clearance. Chapter 2 describes the requirement of 2-O-sulfation of uronic acids in heparan sulfate for binding and uptake of lipoprotein remnants using a mouse model in which the relevant biosynthetic enzyme (Hs2st) was selectively inactivated in hepatocytes. Chapter 3 provides genetic evidence for syndecan-1 as the relevant proteoglycan involved in lipoprotein binding and uptake in the liver. Chapter 4 presents insight into the relative contribution of three receptors, syndecan-1, low-density lipoprotein receptors (LDLR), and low-density lipoprotein-related protein-1 (LRP-1) to hepatic clearance. A new mouse model in which all three hepatocyte lipoprotein receptors have been inactivated is described. These mice accumulated triglycerides and cholesterol, demonstrating that heparan sulfate proteoglycans participate in the clearance of cholesterol-rich lipoproteins as well as triglyceride- rich remnants. Chapter 5 proposes future studies into the application of these findings with regards to human disease