title: Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans.
abstract: The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre⁺ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient [³H]TRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre⁻ versus mutant Ndst1f/fAlbCre⁺ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe⁻/⁻Ndst1f/fAlbCre⁺ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre⁺ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate-dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, UCSD, La Jolla, California 92093-0687, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Gonzales
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.forename: Erin M
authors.initials: EM
authors.lastname: Foley
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D053668:Syndecan-1 / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008074:Lipoproteins; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D014280:Triglycerides