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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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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Autophagy
Hepatocytes
Cholesterol
Endosomes
Sirolimus
Lysosomes
Ezetimibe
Cyclodextrins
Intestinal Mucosa
Homeostasis
Down-Regulation
Cell Membrane
Liver

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Yamamura, T., Ohsaki, Y., Suzuki, M., Shinohara, Y., Tatematsu, T., Cheng, J., ... 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
Yamamura, Takeshi ; Ohsaki, Yuki ; Suzuki, Michitaka ; Shinohara, Yuki ; Tatematsu, Tsuyako ; Cheng, Jinglei ; Okada, Masato ; Ohmiya, Naoki ; Hirooka, Yoshiki ; Goto, Hidemi ; Fujimoto, Toyoshi. / Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1-antitrypsin Z deposition. In: Hepatology. 2014 ; Vol. 59, No. 4. pp. 1591-1599.
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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.",
author = "Takeshi Yamamura and Yuki Ohsaki and Michitaka Suzuki and Yuki Shinohara and Tsuyako Tatematsu and Jinglei Cheng and Masato Okada and Naoki Ohmiya and Yoshiki Hirooka and Hidemi Goto and Toyoshi Fujimoto",
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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, vol. 59, no. 4, pp. 1591-1599. https://doi.org/10.1002/hep.26930

Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1-antitrypsin Z deposition. / Yamamura, Takeshi; Ohsaki, Yuki; Suzuki, Michitaka; Shinohara, Yuki; Tatematsu, Tsuyako; Cheng, Jinglei; Okada, Masato; Ohmiya, Naoki; Hirooka, Yoshiki; Goto, Hidemi; Fujimoto, Toyoshi.

In: Hepatology, Vol. 59, No. 4, 01.01.2014, p. 1591-1599.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1-antitrypsin Z deposition

AU - Yamamura, Takeshi

AU - Ohsaki, Yuki

AU - Suzuki, Michitaka

AU - Shinohara, Yuki

AU - Tatematsu, Tsuyako

AU - Cheng, Jinglei

AU - Okada, Masato

AU - Ohmiya, Naoki

AU - Hirooka, Yoshiki

AU - Goto, Hidemi

AU - Fujimoto, Toyoshi

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

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