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 1

Ndst1 conditional knockout.

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Ndst1 conditional knockout. (A) Gene schematic and Sout...
(A) Gene schematic and Southern blotting strategy for mapping Ndst1 alleles. Filled triangles represent loxP recombination sites; bar indicates target sequence of Ndst1 probe; restriction sites for BglII and HindIII and expected fragment sizes are also indicated. (B) Southern blot to determine Cre-mediated recombination of Ndst1 floxed alleles. Hepatocyte genomic DNA was digested with BglII/HindIII and probed for Ndst1 alleles. The deleted allele gave a BglII/HindIII fragment at 3.2 kb, and the Ndst1f and wild-type alleles gave BglII/HindIII fragments at 2.6 kb. The Ndst1fBglII/HindIII fragment was slightly larger than 2.6 kb due to the inserted 34-bp loxP site. DNA in each lane was isolated from individual mice. Quantification of bands indicated 65%–75% recombination in AlbCre+ hepatocytes. (C) The HS chains are depicted using the indicated symbol nomenclature for the individual sugar residues. Heparinases degrade the chains to disaccharides (dashed lines), which can then be separated according the number and pattern of sulfate groups (Table 1). HS chains from the mutant contain less sulfate and iduronic acid because Ndst1 creates the preferred substrates for epimerization and O-sulfation. The residual sulfation presumably arises from incomplete inactivation of Ndst1 and the expression of Ndst2.