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Inhibition of Niemann‐Pick‐type C1‐like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1‐antitrypsin Z deposition
Author(s) -
Yamamura Takeshi,
Ohsaki Yuki,
Suzuki Michitaka,
Shinohara Yuki,
Tatematsu Tsuyako,
Cheng Jinglei,
Okada Masato,
Ohmiya Naoki,
Hirooka Yoshiki,
Goto Hidemi,
Fujimoto Toyoshi
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26930
Subject(s) - ezetimibe , autophagy , mutant , wild type , chemistry , microbiology and biotechnology , deposition (geology) , biology , biochemistry , cholesterol , apoptosis , gene , paleontology , sediment
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. (H epatology 2014;59:1591‐1599)