title: Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK.
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.
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory of Ion channels, Gwangju Institute Science and Technology, School of Life Sciences, Gwangju 500-712, Republic of Korea.
authors.forename: Kwang Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Department of Clinical Pathology, Daekyeung University, Gyeongsan 712-719, Republic of Korea.
authors.forename: Keuk-Jun
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Roudebush VA Medical Center, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea. Electronic address: wschoi@sch.ac.kr.
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Choi
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic address: selpest@knu.ac.kr.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory of Ion channels, Gwangju Institute Science and Technology, School of Life Sciences, Gwangju 500-712, Republic of Korea. Electronic address: cspark@gist.ac.kr.
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
keywords: Cytokine; Gene expression; Inflammation; PPARα; Steatosis