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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 Lee  ;  Soo Han Bae 
 Free Radical Biology and Medicine, Vol.99 : 520-532, 2016 
Journal Title
 Free Radical Biology and Medicine 
Issue Date
AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Antioxidants/pharmacology* ; Apoptosis ; Diet/adverse effects ; 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 ; 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 ; Oxidative Stress ; Sequestosome-1 Protein/genetics ; Sequestosome-1 Protein/metabolism ; Signal Transduction
AMPK ; Ezetimibe ; NAFLD ; NASH ; Nrf2 ; P62
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
김규리(Kim, Gyuri)
남기택(Nam, Ki Taek)
민병소(Min, Byung Soh)
박정수(Park, Jeong Su) ORCID logo https://orcid.org/0000-0003-4551-4294
배수한(Bae, Soo Han) ORCID logo https://orcid.org/0000-0002-8007-2906
이용호(Lee, Yong Ho) ORCID logo https://orcid.org/0000-0002-6219-4942
차봉수(Cha, Bong Soo) ORCID logo https://orcid.org/0000-0003-0542-2854
한대훈(Han, Dai Hoon) ORCID logo https://orcid.org/0000-0003-2787-7876
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