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

Autor: Hui-Young Lee, Ki Taek Nam, Byung Soh Min, Jae Sung Lee, Yu Seol Lee, Su Haeng Sung, Soo Han Bae, Hye Won Ji, Yong Ho Lee, Moon Joo Lee, Masaaki Komatsu, Joungmok Kim, Bong Soo Cha, Milim Lee, Yoomi Chun, Soohyun Kim, Da Hyun Lee, Dai Hoon Han, Gyuri Kim, Haengdueng Jeong, Jeong Su Park
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
NF-E2-Related Factor 2
Apoptosis
mTORC1
AMP-Activated Protein Kinases
Biology
medicine.disease_cause
digestive system
Biochemistry
Antioxidants
Mice
03 medical and health sciences
0302 clinical medicine
Ezetimibe
Non-alcoholic Fatty Liver Disease
Physiology (medical)
Internal medicine
Sequestosome-1 Protein
Nonalcoholic fatty liver disease
NAD(P)H Dehydrogenase (Quinone)
medicine
Animals
Humans
PI3K/AKT/mTOR pathway
Glutathione Transferase
Kelch-Like ECH-Associated Protein 1
Membrane Transport Proteins
medicine.disease
KEAP1
Cytoprotection
Diet
Mice
Inbred C57BL
Oxidative Stress
030104 developmental biology
Endocrinology
Gene Expression Regulation
Liver
030220 oncology & carcinogenesis
Steatosis
Oxidative stress
Signal Transduction
medicine.drug
Zdroj: Free Radical Biology and Medicine. 99:520-532
ISSN: 0891-5849
Popis: 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.
Databáze: OpenAIRE
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