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Proteoglycans: Arbiters of lipoprotein metabolism

Wednesday, September 11, 2013


Jeffrey D. Esko, Ph.D.
Professor, Department of Cellular and Molecular Medicine
Co-Director, Glycobiology Research & Training Center
University of California, San Diego

Dr. Esko’s laboratory focuses on understanding the structure, biosynthesis, and function of proteoglycans. This work includes using mass spectrometry to do structural studies of heparan sulfate; applying genome-wide methods to identify genes involved in heparan sulfate assembly and lysosomal turnover; analyzing guanidinylated glycosides that act as molecular transporters; studying proteoglycans in lipoprotein metabolism; and analyzing proteoglycans in inflammation.


Recently, genetic experiments in mice identified the heparan sulfate proteoglycan syndecan-1 as an important receptor for the clearance of triglyceride-rich lipoprotein (TRL) in the liver. This binding site for the TRLs consists of a protein core and one or more heparan sulfate chains. Binding depends on the heparan sulfate chains based on the accumulation of plasma TRLs in mice bearing mutations in heparan sulfate biosynthesis. To identify the major apolipoproteins that mediate binding to the heparan sulfate chains, we developed a series of in vitro and in vivo assays. We identified apolipoprotein E and apolipoprotein A5 as the relevant ligands on TRLs. Clearance of TRLs through syndecan-1 is atheroprotective based on the increase in atherosclerosis in knockout mice fed a high-fat diet. Proteoglycans in macrophages also play an atheroprotective role, but not through a clearance mechanism. Instead, one or more proteoglycans on the macrophage keep the cells in a tonic state in response to interferon beta stimulation.

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