Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
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DOI：
10.1172/jci29154
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发表时间：
2007-01-01
影响因子：
15.9
通讯作者：
Esko, Jeffrey D.
中科院分区：
文献类型：
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作者：
MacArthur, Jennifer M.;Bishop, Joseph R.;Esko, Jeffrey D.
我们使用Cre-loxP系统，通过灭活肝细胞中的生物合成基因GlcNAc n -去乙酰化酶/ n -硫转移酶1 (Ndst1)，研究了肝硫酸肝素在富甘油三酯脂蛋白代谢中的作用，结果表明，肝硫酸肝素的磺化减少了约50%。小鼠存活且健康，但它们积累了富含甘油三酯的脂蛋白颗粒，其中含有载脂蛋白b -100、载脂蛋白b -48、载脂蛋白e和载脂蛋白i - iv。与仅缺乏LDL受体的小鼠相比，将这种突变与LDL受体缺乏相结合，会导致富含胆固醇和甘油三酯的颗粒的积累增加，这表明硫酸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VLDL，但血浆清除率降低，肝脏VLDL摄取相应减少。视黄醇酯漂移研究显示肠源性脂蛋白的清除也依赖于肝细胞硫酸肝素。这些结果表明，在正常生理条件下，肝硫酸肝素蛋白聚糖在清除肠源性和肝源性脂蛋白颗粒中起重要作用。
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.