| First Author | Gonzales JC | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 6 | Pages | 2742-51 |
| PubMed ID | 23676495 | Mgi Jnum | J:201440 |
| Mgi Id | MGI:5514108 | Doi | 10.1172/JCI67398 |
| Citation | Gonzales JC, et al. (2013) Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J Clin Invest 123(6):2742-51 |
| abstractText | 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 [(3)H]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. |
