Genetic analysis of proteoglycan-mediated lipoprotein clearance

University Of California, San Diego, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): Genetic Analysis of Proteoglycan-Mediated Lipoprotein Clearance. Patients with hypertriglyceridemia have increased risk for atherosclerosis and coronary artery disease, thus considerable interest exists in understanding its etiology and therapy. Triglyceride accumulation can arise from altered lipid biosynthesis, apolipoproteinemias, alterations in lipolysis in the peripheral circulation, and from defective clearance of lipoprotein remnants in the liver, which occurs through several receptors, including members of the low-density lipoprotein (LDL) receptor family and syndecan-1 (SDC1), a trans-membrane heparan sulfate proteoglycan. Our studies have established that (i) SDC1 is the primary proteoglycan receptor that mediates TRL clearance in mice and human hepatocytes; (ii) SDC1 acts independently of, but in parallel to, the action of LDLR and LRP1; (iii) Docking of TRLs to SDC1 is dose-dependent and saturable; (iv) The HS chains on SDC1 make up the binding site for TRLs; (v) SDC1 clears a distinct subset of small TRL particles; (vi) Docking of TRLs to SDC1 is mediated by interaction of apoE and apoA-V on the particles with the HS chains of SDC1; (vii) Human mutations in EXT1, the heparan sulfate copolymerase, results in mild post-prandial hypertriglyceridemia; (viii) Induced shedding of SDC1 results in hypertriglyceridemia; (ix) Undersulfation of the HS chains on SDC1 exacerbates diet-induced atherosclerosis; (x) Subtle changes in HS composition in macrophages can have a profound effect on diet-induced atherosclerosis and obesity. Recent studies have shown that apoC-III accumulates in mutants lacking the hepatic proteoglycan receptors, suggesting that SDC1 may specialize in the clearance of particles enriched in apoC-III. These findings have led to the central hypothesis of this proposal that SDC1 interacts with subpopulations of lipoproteins of unique apolipoprotein composition in a way that depends on the structure of SDC1 and the heparan sulfate chains. To address this hypothesis, we have the following specific aims: * Aim 1. Test if apoC-III facilitates binding and hepatic clearance of unique subfractions of TRLs and LDL via SDC1. * Aim 2. Examine SDC1 structure-function as related to its capacity to bind and facilitate uptake of human TRLs and formulated particles containing defined ratios of apoE, apoA-V and apoC-III. * Aim 3. Test whether natural variation in HS content or structure in hepatocytes and macrophages could result in differential susceptibility to hyperlipidemia and CVD. Our genetic analysis of HSPGs in the mice and humans support the idea that changes in heparan sulfate could contribute to human dyslipidemias.