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Binge ethanol-induced HDAC3 down-regulates Cpt1? expression leading to hepatic steatosis and injury.

ABSTRACT: BACKGROUND:Recently, we have demonstrated that acute alcohol exposure due to binge drinking leads to hepatic steatosis with the deregulation of hepatic histone deacetylase (HDAC) expression. Various class I, II, and IV HDACs were down-regulated, whereas expression of HDAC3 was solely up-regulated. Hence, in the present work, we specifically examined the mechanistic role of HDAC3 in the development of hepatic steatosis occurring in response to binge alcohol administration. METHODS:C57BL/6 mice were gavaged 3 times with ethanol (EtOH) at a dose of 4.5 g/kg. HDAC inhibitor, Trichostatin A (TSA) was simultaneously injected intraperitoneally at a dose of 1 mg/kg. Hepatic steatosis, injury, expression of HDAC3 and carnitine palmitoyltransferase 1? (CPT1?) were evaluated. HDAC3 and histone H3 acetylation levels at the Cpt1? promoter were analyzed by chromatin immunoprecipitation (ChIP). RESULTS:The binge EtOH-mediated increase in HDAC3 was prevented by simultaneous administration of HDAC inhibitor, TSA, which markedly attenuated hepatic steatosis and injury. Importantly, HDAC3 inhibition was able to normalize the down-regulation of Cpt1? expression. Causal role of HDAC3 in the transcriptional repression of Cpt1? was demonstrated by increased HDAC3 binding at the thyroid receptor element site in the Cpt1? distal promoter region. Further, a resultant decrease in the transcriptionally permissive histone H3 lysine 9 acetylation in the proximal promoter region near the transcriptional start site was observed. Notably, TSA treatment reduced HDAC3 binding and increased H3K9 acetylation at Cpt1? promoter leading to increased Cpt1? expression. These molecular events resulted in attenuation of binge alcohol-induced hepatic steatosis. CONCLUSIONS:These findings provide insights into potential epigenetic mechanisms underlying transcriptional regulation of Cpt1? in the hepatic steatosis occurring in response to binge EtOH administration.

SUBMITTER: Kirpich I

PROVIDER: S-EPMC3975907 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Binge ethanol-induced HDAC3 down-regulates Cpt1α expression leading to hepatic steatosis and injury.

Kirpich Irina I Zhang Jingwen J Gobejishvili Leila L Kharebava Giorgi G Barker David D Ghare Smita S Joshi-Barve Swati S McClain Craig J CJ Barve Shirish S

Alcoholism, clinical and experimental research 20130726 11

<h4>Background</h4>Recently, we have demonstrated that acute alcohol exposure due to binge drinking leads to hepatic steatosis with the deregulation of hepatic histone deacetylase (HDAC) expression. Various class I, II, and IV HDACs were down-regulated, whereas expression of HDAC3 was solely up-regulated. Hence, in the present work, we specifically examined the mechanistic role of HDAC3 in the development of hepatic steatosis occurring in response to binge alcohol administration.<h4>Methods</h4> ...[more]

PMID: 23905631

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Project description:Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activity, attenuates hepatic steatosis and injury. The present study examined the beneficial effect of tributyrin/butyrate in attenuating ethanol-induced pathogenic epigenetic mechanisms affecting CPT-1A promoter-histone modifications and gene expression and hepatic steatosis/injury.MethodsMice were fed a liquid Lieber-DeCarli diet (Research Diet Inc, New Brunswick, NJ) with or without ethanol for 4 weeks. In a subset of mice, tributyrin (2 g/kg) was administered orally by gavage. Primary rat hepatocytes were treated with 50 mmol/L ethanol and/or 2 mmol/L butyrate. Gene expression and epigenetic modifications at the CPT-1A promoter were analyzed by chromatin immunoprecipitation analysis.ResultsIn vivo, ethanol induced hepatic CPT-1A promoter histone H3K9 deacetylation, which is indicative of a repressive chromatin state, and decreased CPT-1A gene expression. Our data identified HDAC1 as the predominant HDAC causing CPT-1A promoter histone H3K9 deacetylation and epigenetic down-regulation of gene expression. Significantly, Specificity Protein 1 (SP1) and Hepatocyte Nuclear Factor 4 Alpha (HNF4α) participated in the recruitment of HDAC1 to the proximal and distal regions of CPT-1A promoter, respectively, and mediated transcriptional repression. Importantly, butyrate, a dietary HDAC inhibitor, attenuated ethanol-induced recruitment of HDAC1 and facilitated p300-HAT binding by enabling SP1/p300 interaction at the proximal region and HNF4α/peroxisomal proliferator-activated receptor-γ coactivator-1α/p300 interactions at the distal region, leading to promoter histone acetylation and enhanced CPT-1A transcription.ConclusionsThis study identifies HDAC1-mediated repressive epigenetic mechanisms that underlie an ethanol-mediated decrease in CPT-1A expression. Importantly, tributyrin/butyrate inhibits HDAC1, rescues CPT-1A expression, and attenuates ethanol-mediated hepatic steatosis and injury, suggesting its potential use in therapeutic strategies for alcoholic liver disease.

Dataset Information

Binge ethanol-induced HDAC3 down-regulates Cpt1? expression leading to hepatic steatosis and injury.

Publications

Binge ethanol-induced HDAC3 down-regulates Cpt1α expression leading to hepatic steatosis and injury.

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