Liver Heparan Sulfate Proteoglycans Mediate Clearance of Triglyceride-rich Lipoproteins Independently of LDL Receptor Family Members

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Jan 4

PMID 17200715

Citations 100

Authors

Jennifer M MacArthur

Joseph R Bishop

Kristin I Stanford

Lianchun Wang

Andre Bensadoun

Joseph L Witztum

Jeffrey D Esko

Affiliations

Soon will be listed here.

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.

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