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J Clin Invest. 2013 Jun;123(6):2742-51. doi: 10.1172/JCI67398. Epub 2013 May 8.

Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans.

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1
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, UCSD, La Jolla, California 92093-0687, USA.

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.

PMID:
23676495
PMCID:
PMC3668842
DOI:
10.1172/JCI67398
[Indexed for MEDLINE]
Free PMC Article
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