Inhibition of NPC1L1 by ezetimibe activates autophagy in human hepatocyte and reduces mutant α1-antitrypsin Z deposition.
Inhibition of NPC1L1 by ezetimibe activates autophagy in human hepatocyte and reduces mutant α1-antitrypsin Z deposition.
复制标题
依折麦布抑制 NPC1L1 可激活人肝细胞中的自噬并减少突变体 α1-抗胰蛋白酶 Z 沉积。
DOI：
10.1002/hep.26930
复制
发表时间：
2014
期刊：
影响因子：
13.5
通讯作者：
Fujimoto T
中科院分区：
文献类型：
--
作者：
Yamamura T;Ohsaki Y;Suzuki M;Shinohara Y;Tatematsu T;Cheng J;Okada M;Ohmiya N;Hirooka Y;Goto H;Fujimoto T
自噬可以降解易聚集蛋白，但过度的自噬会产生不良影响。如果自噬能够以细胞类型特异性的方式增强，这将是有益的，但由于自噬的基本机制是共同的，这一点一直很困难。在本研究中，我们发现依折替米贝对Niemann‐Pick‐type C1‐like 1 （NPC1L1）的抑制作用仅在肝细胞和小肠上皮中激活自噬，而在其他细胞中不起作用。依折替米贝诱导游离胆固醇在晚期内核体/溶酶体中积累，并增加筏中调节成分LAMTOR1的分配。后一种变化导致哺乳动物雷帕霉素靶蛋白（mTOR）C1活性下调，通过减少mTOR向晚期内溶体/溶酶体的募集和激活自噬。ezetimibe的主要作用是降低质膜中的游离胆固醇，因为ezetimibe引起的所有结果都被补充胆固醇作为甲基- β -环糊精复合物所抑制。ezetimibe通过增强人原代肝细胞的自噬，显著降低了不溶性突变体α1‐抗胰蛋白酶Z。结论：依折替米贝抑制NPC1L1通过调节胆固醇稳态激活人肝细胞自噬。依折替米贝可用于改善α1‐抗胰蛋白酶缺乏症患者的肝脏变性。(Hepatology2014; 59:1591公/ 1599)
Autophagy can degrade aggregate‐prone proteins, but excessive autophagy can have adverse effects. It would be beneficial if autophagy could be enhanced in a cell type‐specific manner, but this has been difficult because the basic mechanism of autophagy is common. In the present study we found that inhibition of Niemann‐Pick‐type C1‐like 1 (NPC1L1) by ezetimibe activates autophagy only in hepatocytes and small intestinal epithelia, but not in other cells. Ezetimibe induced accumulation of free cholesterol in the late endosome/lysosome and increased partitioning of a Ragulator component, LAMTOR1, in rafts. The latter change led to down‐regulation of mammalian target of rapamycin (mTOR)C1 activity by decreasing mTOR recruitment to the late endosome/lysosome and activated autophagy. A primary effect of ezetimibe was found to be a decrease of free cholesterol in the plasma membrane, because all the results caused by ezetimibe were suppressed by supplementation of cholesterol as a methyl‐β‐cyclodextrin complex. By enhancing autophagy in human primary hepatocytes with ezetimibe, insoluble mutant α1‐antitrypsin Z was reduced significantly.Conclusion: Inhibition of NPC1L1 by ezetimibe activates autophagy in human hepatocytes by modulating cholesterol homeostasis. Ezetimibe may be used to ameliorate liver degeneration in α1‐antitrypsin deficiency. (Hepatology2014;59:1591‐1599)