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

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

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38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)520-532
Number of pages13
JournalFree Radical Biology and Medicine
Volume99
DOIs
Publication statusPublished - 2016 Oct 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF- 2013R1A1A2059087 ; S.H. Bae) and the Faculty Research Grant of the Yonsei University College of Medicine ( 6-2014-0068 ; S.H. Bae). It was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea ( HI16C0257 ; S.H. Bae and HI14C2476 ; Y.H. Lee) and Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT & Future Planning ( 2015R1C1A1A01052558 ; Y.H. Lee). It was also supported by the Korea Mouse Phenotyping Center, and the Brain Korea 21 PLUS Project for Medical Science, Yonsei University, the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF- 2013M3A9D5072551 ; K.T. Nam). The Korea Healthcare Technology R&D Project , Ministry for Health, Welfare & Family Affairs ( HI14C1135 ; H.Y. Lee). Appendix A

Publisher Copyright:
© 2016 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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