Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice.
Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice.
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DOI：
10.1161/atvbaha.113.301637
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Esko JD
中科院分区：
文献类型：
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作者：
Foley EM;Gordts PLSM;Stanford KI;Gonzales JC;Lawrence R;Stoddard N;Esko JD
乳糜微粒和极低密度脂蛋白残余物通过硫酸乙酰肝素蛋白聚糖（HSPG）受体（syndecan-1）、低密度脂蛋白受体（LDLR）和LDLR相关蛋白-1（LRP 1）从肝脏循环中清除，但在不同饮食条件下每类受体的相对贡献仍不清楚。在AlbCre+ Ndst 1f/f、Ldlr−/−和AlbCre+ Lrp 1f/f小鼠以及含有这些突变组合的小鼠中测量富含甘油三酯的脂蛋白清除率。单突变和双突变小鼠的甘油三酯测量结果表明，HSPGs和LDLR在空腹条件下和餐后条件下占主导地位的清除率，但LRP 1的贡献显着时，LDLR是缺席。缺乏所有三种受体肝脏表达的小鼠（AlbCre+ Ndst 1f/f Lrp 1f/f Ldlr−/−）表现出严重的高脂血症（870 ± 270 mg甘油三酯/dL; 1300 ± 350 mg总胆固醇/dL），并由于肝脏清除率降低而表现出持续的餐后甘油三酯水平升高。对突变体中积累的颗粒的分析表明，HSPG优先清除富含磷脂酰肌醇的小脂蛋白（直径约20-40 nm）的子集，而LDLR和LRP 1清除较大的颗粒（直径约40-60 nm）。最后，我们表明，热休克蛋白G发挥了重要作用，在清除TRL在正常饮食或餐后条件下喂养的小鼠，但似乎发挥不太重要的作用，高脂肪饮食。这些数据表明，HSPG，LDLR和LRP 1清除颗粒的不同子集，HSPG独立于LDLR和LRP 1工作，HSPG，LDLR和LRP 1是小鼠中三种主要的肝脏TRL清除受体。
Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear. Triglyceride-rich lipoprotein clearance was measured in AlbCre+Ndst1f/f, Ldlr−/−, and AlbCre+Lrp1f/f mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all three receptors (AlbCre+Ndst1f/f Lrp1f/f Ldlr−/−) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels due to reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (~20-40 nm diameter), while LDLR and LRP1 clear larger particles (~40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of TRLs in mice fed normal chow or under postprandial conditions but appear to play a less significant role on a high fat diet. These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently from LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the three major hepatic TRL clearance receptors in mice.