Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1-antitrypsin Z deposition

Takeshi Yamamura, Yuki Ohsaki, Michitaka Suzuki, Yuki Shinohara, Tsuyako Tatematsu, Jinglei Cheng, Masato Okada, Naoki Ohmiya, Yoshiki Hirooka, Hidemi Goto, Toyoshi Fujimoto

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Abstract

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.

Original languageEnglish
Pages (from-to)1591-1599
Number of pages9
JournalHepatology
Volume59
Issue number4
DOIs
Publication statusPublished - 01-01-2014
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Yamamura, T., Ohsaki, Y., Suzuki, M., Shinohara, Y., Tatematsu, T., Cheng, J., Okada, M., Ohmiya, N., Hirooka, Y., Goto, H., & Fujimoto, T. (2014). Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1-antitrypsin Z deposition. Hepatology, 59(4), 1591-1599. https://doi.org/10.1002/hep.26930