MacArthur Jennifer M, Bishop Joseph R, Stanford Kristin I, Wang Lianchun, Bensadoun André, Witztum Joseph L, Esko Jeffrey D
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093-0687, USA.
J Clin Invest. 2007 Jan;117(1):153-64. doi: 10.1172/JCI29154.
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.
我们通过使用Cre-loxP系统使肝细胞中的生物合成基因N-乙酰葡糖胺N-脱乙酰酶/N-磺基转移酶1（Ndst1）失活，研究了肝硫酸乙酰肝素在富含甘油三酯的脂蛋白代谢中的作用，这导致肝脏硫酸乙酰肝素的硫酸化减少了约50%。小鼠存活且健康，但它们积累了含有载脂蛋白B-100、载脂蛋白B-48、载脂蛋白E和载脂蛋白CI-IV的富含甘油三酯的脂蛋白颗粒。与仅缺乏低密度脂蛋白受体的小鼠相比，将该突变与低密度脂蛋白受体缺陷相结合会导致富含胆固醇和甘油三酯的颗粒积累增加，这表明硫酸乙酰肝素也参与了富含胆固醇的脂蛋白的清除。突变小鼠正常合成极低密度脂蛋白（VLDL），但显示出对人VLDL的血浆清除率降低，以及肝脏VLDL摄取相应减少。视黄酯漂移研究表明，肠道来源脂蛋白的清除也依赖于肝细胞硫酸乙酰肝素。这些发现表明，在正常生理条件下，肝硫酸乙酰肝素蛋白聚糖在肠道来源和肝脏脂蛋白颗粒的清除中起关键作用。
