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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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

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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    Lee, D. H., Han, D. H., Nam, K. T., Park, J. S., Kim, S. H., Lee, M., Kim, G., Min, B. S., Cha, B. S., Lee, Y. S., Sung, S. H., Jeong, H., Ji, H. W., Lee, M. J., Lee, J. S., Lee, H. Y., Chun, Y., Kim, J., Komatsu, M., ... Bae, S. H. (2016). Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radical Biology and Medicine, 99, 520-532. https://doi.org/10.1016/j.freeradbiomed.2016.09.009