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

Yong Deuk Kim, Kwang Min Lee, Seung Lark Hwang, Hyeun Wook Chang, Keuk Jun Kim, Robert A. Harris, Hueng Sik Choi, Won Sik Choi, Sung Eun Lee, Chul Seung Park

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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 α (PPARα) 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 PPARα 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 PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα 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.

Original languageEnglish (US)
Pages (from-to)2662-2670
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Cytokine
  • Gene expression
  • Inflammation
  • PPARα
  • Steatosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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    Kim, Y. D., Lee, K. M., Hwang, S. L., Chang, H. W., Kim, K. J., Harris, R. A., Choi, H. S., Choi, W. S., Lee, S. E., & Park, C. S. (2015). Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1852(12), 2662-2670. https://doi.org/10.1016/j.bbadis.2015.09.014