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

• Published in: Free radical biology & medicine 2016-10, Vol.99, p.520-532
• Main Authors: Lee, Da Hyun, Han, Dai Hoon, Nam, Ki Taek, Park, Jeong Su, Kim, Soo Hyun, Lee, Milim, Kim, Gyuri, Min, Byung Soh, Cha, Bong-Soo, Lee, Yu Seol, Sung, Su Haeng, Jeong, Haengdueng, Ji, Hye Won, Lee, Moon Joo, Lee, Jae Sung, Lee, Hui-Young, Chun, Yoomi, Kim, Joungmok, Komatsu, Masaaki, Lee, Yong-ho, Bae, Soo Han
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Antioxidants - pharmacology; Apoptosis; Diet - adverse effects; Ezetimibe; Ezetimibe - pharmacology; Gene Expression Regulation; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Humans; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Inbred C57BL; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NAFLD; NASH; NF-E2-Related Factor 2 - agonists; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Nrf2; Oxidative Stress; P62; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Signal Transduction
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.09.009

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. [Display omitted] •Ezetimibe acts as a potent Nrf2 activator without causing cytotoxicity.•Ezetimibe-induced Nrf2 activation is mainly dependent on phosphorylation of p62.•AMPK is required for ezetimibe-induced phosphorylation of p62 and Nrf2 activation.•Ezetimibe protects mice from nonalcoholic steatohepatitis through Nrf2 activation.