Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA.
Department of Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA.
Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2065-74. doi: 10.1161/ATVBAHA.113.301637. Epub 2013 Jul 11.
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(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/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 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of 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), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem 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 of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.
乳糜微粒和极低密度脂蛋白残粒通过硫酸乙酰肝素蛋白聚糖（HSPG）受体（连接蛋白-1）、低密度脂蛋白受体（LDLR）和 LDLR 相关蛋白-1（LRP1）从循环中清除，但在不同饮食条件下，每种受体的相对贡献仍不清楚。
在 AlbCre(+)Ndst1(f/f)、Ldlr(-/-)和 AlbCre(+)Lrp1(f/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。在单突变和双突变小鼠中进行甘油三酯测量表明，HSPG 和 LDLR 在空腹和餐后条件下主导清除，而在 LDLR 缺失时 LRP1 贡献显著。缺乏肝脏表达所有 3 种受体（AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)）的小鼠表现出明显的高脂血症（870 ± 270 mg 甘油三酯/dL；1300 ± 350 mg 总胆固醇/dL），并由于肝清除减少而表现出持续升高的餐后甘油三酯水平。对在突变体中积累的颗粒进行分析表明，HSPG 优先清除一小部分富含甘油三酯的小脂蛋白（≈20-40nm 直径），而 LDLR 和 LRP1 则清除较大的颗粒（≈40-60nm 直径）。最后，我们表明 HSPG 在正常饲料喂养或餐后条件下的小鼠中清除富含甘油三酯的脂蛋白中起主要作用，但在高脂肪饮食中似乎作用较小。
这些数据表明 HSPG、LDLR 和 LRP1 清除不同的颗粒亚群，HSPG 独立于 LDLR 和 LRP1 发挥作用，HSPG、LDLR 和 LRP1 是小鼠中 3 种主要的肝脏富含甘油三酯的脂蛋白清除受体。
