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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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

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Nutrition
Oxidative stress
Diet
Liver
Oxidative Stress
Antioxidants
Proteins
AMP-Activated Protein Kinases
Biomarkers
Cell death
Cytotoxicity
Choline
Cytoprotection
Autophagy
In Situ Nick-End Labeling
United States Food and Drug Administration
Ezetimibe
Non-alcoholic Fatty Liver Disease
Hypercholesterolemia
Fatty Acids

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

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. / Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. In: Free Radical Biology and Medicine. 2016 ; Vol. 99. pp. 520-532.
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title = "Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis",
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.",
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Lee, DH, Han, DH, Nam, KT, Park, JS, Kim, SH, Lee, M, Kim, G, Min, BS, Cha, BS, Lee, YS, Sung, SH, Jeong, H, Ji, HW, Lee, MJ, Lee, JS, Lee, HY, Chun, Y, Kim, J, Komatsu, M, Lee, YH & Bae, SH 2016, 'Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis', Free Radical Biology and Medicine, vol. 99, pp. 520-532. https://doi.org/10.1016/j.freeradbiomed.2016.09.009

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

In: Free Radical Biology and Medicine, Vol. 99, 01.10.2016, p. 520-532.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis

AU - Lee, Da Hyun

AU - Han, Dai Hoon

AU - Nam, Ki Taek

AU - Park, Jeong Su

AU - Kim, Soo Hyun

AU - Lee, Milim

AU - Kim, Gyuri

AU - Min, Byung Soh

AU - Cha, Bong Soo

AU - Lee, Yu Seol

AU - Sung, Su Haeng

AU - Jeong, Haengdueng

AU - Ji, Hye Won

AU - Lee, Moon Joo

AU - Lee, Jae Sung

AU - Lee, Hui Young

AU - Chun, Yoomi

AU - Kim, Joungmok

AU - Komatsu, Masaaki

AU - Lee, Yong ho

AU - Bae, Soo Han

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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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