Wang Yan, McNutt Markey C, Banfi Serena, Levin Michael G, Holland William L, Gusarova Viktoria, Gromada Jesper, Cohen Jonathan C, Hobbs Helen H
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11630-5. doi: 10.1073/pnas.1515374112. Epub 2015 Aug 24.
Angiopoietin-like protein 3 (ANGPTL3) is a circulating inhibitor of lipoprotein and endothelial lipase whose physiological function has remained obscure. Here we show that ANGPTL3 plays a major role in promoting uptake of circulating very low density lipoprotein-triglycerides (VLDL-TGs) into white adipose tissue (WAT) rather than oxidative tissues (skeletal muscle, heart brown adipose tissue) in the fed state. This conclusion emerged from studies of Angptl3(-/-) mice. Whereas feeding increased VLDL-TG uptake into WAT eightfold in wild-type mice, no increase occurred in fed Angptl3(-/-) animals. Despite the reduction in delivery to and retention of TG in WAT, fat mass was largely preserved by a compensatory increase in de novo lipogenesis in Angptl3(-/-) mice. Glucose uptake into WAT was increased 10-fold in KO mice, and tracer studies revealed increased conversion of glucose to fatty acids in WAT but not liver. It is likely that the increased uptake of glucose into WAT explains the increased insulin sensitivity associated with inactivation of ANGPTL3. The beneficial effects of ANGPTL3 deficiency on both glucose and lipoprotein metabolism make it an attractive therapeutic target.
血管生成素样蛋白3(ANGPTL3)是一种循环脂蛋白和内皮脂肪酶抑制剂,其生理功能一直不明。我们在此表明,ANGPTL3在促进进食状态下循环极低密度脂蛋白甘油三酯(VLDL-TG)摄取进入白色脂肪组织(WAT)而非氧化组织(骨骼肌、心脏、棕色脂肪组织)中起主要作用。这一结论来自对Angptl3(-/-)小鼠的研究。在野生型小鼠中,进食使VLDL-TG摄取进入WAT增加了8倍,而在进食的Angptl3(-/-)动物中则没有增加。尽管进入WAT的TG输送和潴留减少,但Angptl3(-/-)小鼠通过从头脂肪生成的代偿性增加,脂肪量基本得以保留。在基因敲除小鼠中,WAT的葡萄糖摄取增加了10倍,示踪研究显示WAT而非肝脏中葡萄糖向脂肪酸的转化增加。WAT中葡萄糖摄取增加可能解释了与ANGPTL3失活相关的胰岛素敏感性增加。ANGPTL3缺乏对葡萄糖和脂蛋白代谢的有益作用使其成为一个有吸引力的治疗靶点。