Hepatocyte Syndecan 1 Mediates Triglyceride‐Rich Lipoprotein Clearance in the Liver

Abstract

We previously provided genetic evidence that alterations in heparan sulfate fine structure result in an accumulation of plasma triglyceride‐rich lipoproteins (MacArthur et al, J. Clin. Invest. 117:153, 2007). In this study, we sought to determine which heparan sulfate proteoglycans play a role in triglyceride‐rich lipoprotein metabolism. RT‐PCR analysis of hepatocytes demonstrated the expression of the membrane proteoglycans syndecans‐1, ‐2, and ‐4, glypicans‐1 and ‐4, and the secreted proteoglycans agrin, perlecan, and collagen XVIII. Analysis of available mice deficient in the various proteoglycans showed that only syndecan 1 and collagen XVIII mutants accumulated plasma triglycerides. Furthermore the extent of accumulation was comparable to that observed in heparan sulfate deficient strains. Immunoelectron microscopy showed expression of syndecan‐1 on plasma membrane microvilli of hepatocyte basal membranes lining the space of Disse. Mice deficient in syndecan‐1 synthesized VLDL normally, but exhibited reduced uptake of injected VLDL. Retinyl ester excursion studies showed that clearance of intestinally derived lipoproteins also depended on syndecan‐1. In contrast, collagen XVIII deficient mice did not show a defect in hepatic clearance, but rather a change in metabolism of lipoproteins in the peripheral circulation. These findings show that syndecan 1 is an hepatic proteoglycan receptor mediating the clearance of both intestinally derived and hepatic lipoprotein particles.