Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
Jennifer M. MacArthur, … , Joseph L. Witztum, Jeffrey D. Esko
Jennifer M. MacArthur, … , Joseph L. Witztum, Jeffrey D. Esko
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):153-164. https://doi.org/10.1172/JCI29154.
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Research Article

Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members

Abstract

We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.

Authors

Jennifer M. MacArthur, Joseph R. Bishop, Kristin I. Stanford, Lianchun Wang, André Bensadoun, Joseph L. Witztum, Jeffrey D. Esko

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Figure 7

Model of possible roles for hepatic HS in TRL clearance.

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Model of possible roles for hepatic HS in TRL clearance. Hepatocytes and...
Hepatocytes and endothelial cells produce membrane-bound HSPGs and secrete proteoglycans into the space of Disse. After lipolytic processing of lipoproteins in the circulation by Lpl (blue triangles), apoE-enriched (black circles) remnant lipoproteins enter the space of Disse through fenestrations in the endothelium. Remnant lipoproteins are thought to be sequestered near the hepatocyte cell surface via apoE-HS binding or lipase-HS bridging on secreted HSPGs. Lipoproteins are further processed in the space of Disse by transfer of soluble apoE (gray circles) and by HL (red triangles) bound via HS. apoE, HL, and Lpl can potentially serve as ligands of TRLs. Endocytosis of lipoprotein particles occurs via LDLR (blue) or LRP (purple) in association with HSPGs or independently by proteoglycans. Adapted with permission from Journal of Lipid Research (8) and Arteriosclerosis, Thrombosis, and Vascular Biology (86).