title: Binge ethanol-induced HDAC3 down-regulates Cpt1α 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 1α (CPT1α) were evaluated. HDAC3 and histone H3 acetylation levels at the Cpt1α 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 Cpt1α expression. Causal role of HDAC3 in the transcriptional repression of Cpt1α was demonstrated by increased HDAC3 binding at the thyroid receptor element site in the Cpt1α 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 Cpt1α promoter leading to increased Cpt1α 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 Cpt1α in the hepatic steatosis occurring in response to binge EtOH administration.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition , Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Alcohol Research Center , Louisville, Kentucky.
authors.forename: Irina
authors.initials: I
authors.lastname: Kirpich
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.forename: David
authors.initials: D
authors.lastname: Barker
authors.forename: Smita
authors.initials: S
authors.lastname: Ghare
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000235:genetics / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D000431:Ethanol / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000099186:Histone Deacetylase 3
chemical_list: D002334:Carnitine O-Palmitoyltransferase; D002492:Central Nervous System Depressants; D000431:Ethanol; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3
keywords: Binge Alcohol Exposure; CPT1α; HDAC3; Liver Steatosis
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