Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis

Free Radical Biology and Medicine

Volumn 99, Issue , 2016, Pages 520-532

  Lee, Da Hyun ^a,b   Han, Dai Hoon ^b   Nam, Ki Taek ^a,b   Park, Jeong Su ^b   Kim, Soo Hyun ^b   Lee, Milim ^b   Kim, Gyuri ^b   Min, Byung Soh ^b   Cha, Bong Soo ^b   Lee, Yu Seol ^b   Sung, Su Haeng ^b   Jeong, Haengdueng ^a,b   Ji, Hye Won ^b   Lee, Moon Joo ^b   Lee, Jae Sung ^c   Lee, Hui Young ^c   Chun, Yoomi ^e   Kim, Joungmok ^e   Komatsu, Masaaki ^d   Lee, Yong ho ^b   Bae, Soo Han ^b   more..

^a Yonsei University   (South Korea)

^b Yonsei University College of Medicine   (South Korea)

^c Gachon University   (South Korea)

^d NIIGATA UNIVERSITY GRADUATE SCHOOL OF MEDICAL AND DENTAL SCIENCES   (Japan)

^e Kyung Hee University   (South Korea)

Author keywords

AMPK; Ezetimibe; NAFLD; NASH; Nrf2; P62

Indexed keywords

ANTIOXIDANT; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MESSENGER RNA; PROTEIN P62; SATURATED FATTY ACID; TRANSCRIPTION FACTOR NRF2; CARRIER PROTEIN; GLUTATHIONE TRANSFERASE; GSTA1 PROTEIN, HUMAN; KEAP1 PROTEIN, MOUSE; NFE2L2 PROTEIN, MOUSE; NPC1L1 PROTEIN, MOUSE; NQO1 PROTEIN, HUMAN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) DEHYDROGENASE (QUINONE); SEQUESTOSOME 1; SQSTM1 PROTEIN, MOUSE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIOXIDANT ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; CELL PROTECTION; HEK293 CELL LINE; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; HUMAN TISSUE; IN VITRO STUDY; KINASE ASSAY; LIVER CELL; MALE; MOUSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; AGONISTS; ANIMAL; C57BL MOUSE; DIET; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; LIVER; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; ANTIOXIDANTS; APOPTOSIS; DIET; EZETIMIBE; GENE EXPRESSION REGULATION; GLUTATHIONE TRANSFERASE; HUMANS; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; LIVER; MALE; MEMBRANE TRANSPORT PROTEINS; MICE; MICE, INBRED C57BL; NAD(P)H DEHYDROGENASE (QUINONE); NF-E2-RELATED FACTOR 2; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; SEQUESTOSOME-1 PROTEIN; SIGNAL TRANSDUCTION;

EID: 84987932364     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2016.09.009     Document Type: Article

References (42)

1. [1] Postic, C., Girard, J., Contribution of dea novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Investig. 118 (2008), 829–838.
2. [2] Browning, J.D., Horton, J.D., Molecular mediators of hepatic steatosis and liver injury. J. Clin. Investig. 114 (2004), 147–152.
3. [3] Kensler, T.W., Wakabayashi, N., Biswal, S., Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev. Pharmacol. Toxicol. 47 (2007), 89–116.
4. [4] Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.S., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K., Yamamoto, M., The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12 (2010), 213–223.
5. [5] Taguchi, K., Motohashi, H., Yamamoto, M., Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16 (2011), 123–140.
6. [6] Ichimura, Y., Waguri, S., Sou, Y.S., Kageyama, S., Hasegawa, J., Ishimura, R., Saito, T., Yang, Y., Kouno, T., Fukutomi, T., Hoshii, T., Hirao, A., Takagi, K., Mizushima, T., Motohashi, H., Lee, M.S., Yoshimori, T., Tanaka, K., Yamamoto, M., Komatsu, M., Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51 (2013), 618–631.
7. [7] Komatsu, M., Kageyama, S., Ichimura, Y., p62/SQSTM1/A170: physiology and pathology. Pharmacol. Res. 66 (2012), 457–462.
8. [8] Bae, S.H., Sung, S.H., Oh, S.Y., Lim, J.M., Lee, S.K., Park, Y.N., Lee, H.E., Kang, D., Rhee, S.G., Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. 17 (2013), 73–84.
9. [9] Jia, L., Betters, J.L., Yu, L., Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu. Rev. Physiol. 73 (2011), 239–259.
10. [10] M.H. Ahmed, R.A. Saad, M.M. Osman, Ezetimibe: effective and safe treatment for dyslipidaemia associated with nonalcoholic fatty liver disease. Response to: Toth PP, Davidson MH: simvastatin and ezetimibe: combination therapy for the management of dyslipidaemia. Expert Opin. Pharmacother. (2005) 6(1):131-139, Expert Opin.Drug Safety 5: 487-8; 2006.
11. [11] Nozaki, Y., Fujita, K., Yoneda, M., Wada, K., Shinohara, Y., Takahashi, H., Kirikoshi, H., Inamori, M., Kubota, K., Saito, S., Mizoue, T., Masaki, N., Nagashima, Y., Terauchi, Y., Nakajima, A., Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease. J. Hepatol. 51 (2009), 548–556.
12. [12] Park, H., Shima, T., Yamaguchi, K., Mitsuyoshi, H., Minami, M., Yasui, K., Itoh, Y., Yoshikawa, T., Fukui, M., Hasegawa, G., Nakamura, N., Ohta, M., Obayashi, H., Okanoue, T., Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J. Gastroenterol. 46 (2011), 101–107.
13. [13] Zheng, S., Hoos, L., Cook, J., Tetzloff, G., Davis, H. Jr., van Heek, M., Hwa, J.J., Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur. J. Pharmacol. 584 (2008), 118–124.
14. [14] Deushi, M., Nomura, M., Kawakami, A., Haraguchi, M., Ito, M., Okazaki, M., Ishii, H., Yoshida, M., Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett. 581 (2007), 5664–5670.
15. [15] Sugizaki, T., Watanabe, M., Horai, Y., Kaneko-Iwasaki, N., Arita, E., Miyazaki, T., Morimoto, K., Honda, A., Irie, J., Itoh, H., The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice. Endocrinology 155 (2014), 2810–2819.
16. [16] Van Rooyen, D.M., Gan, L.T., Yeh, M.M., Haigh, W.G., Larter, C.Z., Ioannou, G., Teoh, N.C., Farrell, G.C., Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J. Hepatol. 59 (2013), 144–152.
17. [17] Takahashi, Y., Fukusato, T., Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J. Gastroenterol. 20 (2014), 15539–15548.
18. [18] Hernandez-Mijares, A., Banuls, C., Rovira-Llopis, S., Diaz-Morales, N., Escribano-Lopez, I., de Pablo, C., Alvarez, A., Veses, S., Rocha, M., Victor, V.M., Effects of simvastatin, ezetimibe and simvastatin/ezetimibe on mitochondrial function and leukocyte/endothelial cell interactions in patients with hypercholesterolemia. Atherosclerosis 247 (2016), 40–47.
19. [19] Taguchi, K., Fujikawa, N., Komatsu, M., Ishii, T., Unno, M., Akaike, T., Motohashi, H., Yamamoto, M., Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl. Acad. Sci. USA 109 (2012), 13561–13566.
20. [20] Jain, A., Lamark, T., Sjottem, E., Larsen, K.B., Awuh, J.A., Overvatn, A., McMahon, M., Hayes, J.D., Johansen, T., p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285 (2010), 22576–22591.
21. [21] Yamamura, T., Ohsaki, Y., Suzuki, M., Shinohara, Y., Tatematsu, T., Cheng, J., Okada, M., Ohmiya, N., Hirooka, Y., Goto, H., Fujimoto, T., Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant alpha1-antitrypsin Z deposition. Hepatology 59 (2014), 1591–1599.
22. [22] Inoki, K., Zhu, T., Guan, K.L., TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 (2003), 577–590.
23. [23] Park, J.S., Kang, D.H., Lee da, H., Bae, S.H., Concerted action of p62 and Nrf2 protects cells from palmitic acid-induced lipotoxicity. Biochem. Biophys. Res. Commun. 466 (2015), 131–137.
24. [24] Kumashiro, N., Erion, D.M., Zhang, D., Kahn, M., Beddow, S.A., Chu, X., Still, C.D., Gerhard, G.S., Han, X., Dziura, J., Petersen, K.F., Samuel, V.T., Shulman, G.I., Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl. Acad. Sci. USA 108 (2011), 16381–16385.
25. [25] Serviddio, G., Bellanti, F., Vendemiale, G., Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radic. Biol. Med. 65 (2013), 952–968.
26. [26] Sugimoto, H., Okada, K., Shoda, J., Warabi, E., Ishige, K., Ueda, T., Taguchi, K., Yanagawa, T., Nakahara, A., Hyodo, I., Ishii, T., Yamamoto, M., Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 298 (2010), G283–G294.
27. [27] Okada, K., Warabi, E., Sugimoto, H., Horie, M., Gotoh, N., Tokushige, K., Hashimoto, E., Utsunomiya, H., Takahashi, H., Ishii, T., Yamamoto, M., Shoda, J., Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J. Gastroenterol. 48 (2013), 620–632.
28. [28] Chowdhry, S., Nazmy, M.H., Meakin, P.J., Dinkova-Kostova, A.T., Walsh, S.V., Tsujita, T., Dillon, J.F., Ashford, M.L., Hayes, J.D., Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biol. Med. 48 (2010), 357–371.
29. [29] Musso, G., Cassader, M., Gambino, R., Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat. Rev. Drug Discov. 15 (2016), 249–274.
30. [30] Nomura, M., Ishii, H., Kawakami, A., Yoshida, M., Inhibition of hepatic Niemann-Pick C1-like 1 improves hepatic insulin resistance. Am. J. Physiol. Endocrinol. Metab. 297 (2009), E1030–E1038.
31. [31] Chen, W., Sun, Z., Wang, X.J., Jiang, T., Huang, Z., Fang, D., Zhang, D.D., Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol. Cell 34 (2009), 663–673.
32. [32] Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M., Nukina, N., Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell 44 (2011), 279–289.
33. [33] Lim, J., Lachenmayer, M.L., Wu, S., Liu, W., Kundu, M., Wang, R., Komatsu, M., Oh, Y.J., Zhao, Y., Yue, Z., Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet., 11, 2015, e1004987.
34. [34] Yuan, H.X., Xiong, Y., Guan, K.L., Nutrient sensing, metabolism, and cell growth control. Mol. Cell 49 (2013), 379–387.
35. [35] Simons, L., Tonkon, M., Masana, L., Maccubbin, D., Shah, A., Lee, M., Gumbiner, B., Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome. Curr. Med. Res. Opin. 20 (2004), 1437–1445.
36. [36] Yamagishi, S., Nakamura, K., Matsui, T., Sato, T., Takeuchi, M., Inhibition of intestinal cholesterol absorption by ezetimibe is a novel therapeutic target for fatty liver. Med. Hypotheses 66 (2006), 844–846.
37. [37] Takeshita, Y., Takamura, T., Honda, M., Kita, Y., Zen, Y., Kato, K., Misu, H., Ota, T., Nakamura, M., Yamada, K., Sunagozaka, H., Arai, K., Yamashita, T., Mizukoshi, E., Kaneko, S., The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57 (2014), 878–890.
38. [38] Chang, E., Kim, L., Park, S.E., Rhee, E.J., Lee, W.Y., Oh, K.W., Park, S.W., Park, C.Y., Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J. Gastroenterol. 21 (2015), 7754–7763.
39. [39] Puri, P., Baillie, R.A., Wiest, M.M., Mirshahi, F., Choudhury, J., Cheung, O., Sargeant, C., Contos, M.J., Sanyal, A.J., A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46 (2007), 1081–1090.
40. [40] Malhi, H., Bronk, S.F., Werneburg, N.W., Gores, G.J., Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J. Biol. Chem. 281 (2006), 12093–12101.
41. [41] Lambertucci, R.H., Hirabara, S.M., Silveira Ldos, R., Levada-Pires, A.C., Curi, R., Pithon-Curi, T.C., Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells. J. Cell Physiol. 216 (2008), 796–804.
42. [42] Mei, S., Ni, H.M., Manley, S., Bockus, A., Kassel, K.M., Luyendyk, J.P., Copple, B.L., Ding, W.X., Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339 (2011), 487–498.