Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Kim, Yong Deuk¹  Lee, Kwang Min^2,3,4  Hwang, Seung-Lark⁵  Chang, Hyeun Wook⁵  Kim, Keuk-Jun⁶  Harris, Robert A.⁷  Choi, Won-Sik^8,9  Lee, Sung-Eun¹  Park, Chul-Seung^2,3,4 

[1] Kyungpook Natl Univ, Sch Appl Biosci, Daegu 702701, South Korea

[2] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju 500712, South Korea

[3] Gwangju Inst Sci & Technol, Sch Life Sci, Cell Dynam Res Ctr, Gwangju 500712, South Korea

[4] Gwangju Inst Sci & Technol, Sch Life Sci, Natl Leading Res Lab Ion Channels, Gwangju 500712, South Korea

[5] Yeungnam Univ, Coll Pharm, Gyongsan 712749, South Korea

[6] Daekyeung Univ, Dept Clin Pathol, Gyongsan 712719, South Korea

[7] Indiana Univ Sch Med, Roudebush VA Med Ctr, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[8] Chonnam Natl Univ, Natl Creat Res Initiat Ctr Nucl Receptor Signals, Hormone Res Ctr, Sch Biol Sci & Technol, Gwanju 500757, South Korea

[9] Soonchunhyang Univ, Dept Biotechnol, Coll Nat Sci, Asan 336745, Chungnam, South Korea

关键词: Cytokine;    Gene expression;    Inflammation;    PPAR alpha;    Steatosis;   

DOI  :  10.1016/j.bbadis.2015.09.014

来源: Elsevier

【 摘 要 】

Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPAR alpha null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPAR alpha null mice. Fenofibrate increased the recruitment of PPAR alpha on CRBN gene promoter in WT mice but not in PPAR alpha null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPAR alpha by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease. (C) 2015 Elsevier B.V. All rights reserved.

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