title: Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis.
abstract: Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH.
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Da Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Dai Hoon
authors.initials: DH
authors.lastname: Han
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Milim
authors.initials: M
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Gyuri
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Byung Soh
authors.initials: BS
authors.lastname: Min
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Bong-Soo
authors.initials: BS
authors.lastname: Cha
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Yu Seol
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Su Haeng
authors.initials: SH
authors.lastname: Sung
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University; Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Haengdueng
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Ji
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Moon Joo
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, School of Medicine, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, School of Medicine, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Yoomi
authors.initials: Y
authors.lastname: Chun
authors.affiliation: Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Joungmok
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: yholee@yuhs.ac.
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: soohanbae@yuhs.ac.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D004032:Diet / Q000009:adverse effects; D000069438:Ezetimibe / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D026901:Membrane Transport Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C482445:Npc1l1 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D055372:AMP-Activated Protein Kinases; D000069438:Ezetimibe
keywords: AMPK; Ezetimibe; NAFLD; NASH; Nrf2; P62