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

Authors
 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 
Citation
 FREE RADICAL BIOLOGY AND MEDICINE, Vol.99 : 520-532, 2016 
Journal Title
FREE RADICAL BIOLOGY AND MEDICINE
ISSN
 0891-5849 
Issue Date
2016
MeSH
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
Keywords
AMPK ; Ezetimibe ; NAFLD ; NASH ; Nrf2 ; P62
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0891584916304233?via%3Dihub
DOI
10.1016/j.freeradbiomed.2016.09.009
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gyuri(김규리)
Nam, Ki Taek(남기택)
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Park, Jeong Su(박정수) ORCID logo https://orcid.org/0000-0003-4551-4294
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Lee, Da Hyun(이다현) ORCID logo https://orcid.org/0000-0002-5412-6878
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/152286
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