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.
Jennifer M. MacArthur, Joseph R. Bishop, Kristin I. Stanford, Lianchun Wang, André Bensadoun, Joseph L. Witztum, Jeffrey D. Esko
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Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications
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PLoS genetics | 2012 |
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The Journal of neuroscience : the official journal of the Society for Neuroscience | 2009 |
The Recovery Time Course of the Endothelial Cell Glycocalyx In Vivo and Its Implications In Vitro
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The Journal of biological chemistry | 2008 |
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Biochemistry | 2008 |
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Tetrasulfated disaccharide unit in heparan sulfate: enzymatic formation and tissue distribution
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The Journal of biological chemistry | 2008 |
Altered heparan sulfate structure in mice with deleted NDST3 gene function
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The Journal of biological chemistry | 2008 |
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Journal of lipid research | 2008 |
A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation
JP Frederick, AT Tafari, SM Wu, LC Megosh, ST Chiou, RP Irving, JD York |
Proceedings of the National Academy of Sciences | 2008 |
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Robert W. Mahley, Yadong Huang |
Journal of Clinical Investigation | 2007 |