Binge Alcohol-Induced Microvesicular Liver Steatosis and Injury are Associated with Down-Regulation of Hepatic Hdac 1, 7, 9, 10, 11 and Up-Regulation of Hdac 3

Irina Kirpich, Smita Ghare, Jingwen Zhang, Leila Gobejishvili, Giorgi Kharebava, Swati Joshi Barve, David Barker, Akshata Moghe, Craig J. McClain, Shirish Barve

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Background: Binge, as well as chronic, alcohol consumption affects global histone acetylation leading to changes in gene expression. It is becoming increasingly evident that these histone-associated epigenetic modifications play an important role in the development of alcohol-mediated hepatic injury. Methods: C57BL/6 mice were gavaged 3 times (12-hour intervals) with ethanol (EtOH; 4.5 g/kg). Hepatic histone deacetylase (Hdac) mRNAs were assessed by qRT-PCR. Total HDAC activity was estimated by a colorimetric HDAC activity/inhibition assay. Histone acetylation levels were evaluated by Western blot. Liver steatosis and injury were evaluated by histopathology, plasma aminotransferase (ALT) activity, and liver triglyceride accumulation. Expression of fatty acid synthase (Fas) and carnitine palmitoyl transferase 1a (Cpt1a) was also examined. HDAC 9 association with Fas promoter was analyzed. Results: Binge alcohol exposure resulted in alterations of hepatic Hdac mRNA levels. Down-regulation of HDAC Class I (Hdac 1), Class II (Hdac 7, 9, 10), and Class IV (Hdac 11) and up-regulation of HDAC Class I (Hdac 3) gene expression were observed. Correspondent to the decrease in HDAC activity, an increase in hepatic histone acetylation was observed. These molecular events were associated with microvesicular hepatic steatosis and injury characterized by increased hepatic triglycerides (48.02 ± 3.83 vs. 19.90 ± 3.48 mg/g liver, p < 0.05) and elevated plasma ALT activity (51.98 ± 6.91 vs. 20.8 ± 0.62 U/l, p < 0.05). Hepatic steatosis was associated with an increase in FAS and a decrease in CPT1a mRNA and protein expression. Fas promoter analysis revealed that binge EtOH treatment decreased HDAC 9 occupancy at the Fas promoter resulting in its transcriptional activation. Conclusions: Deregulation of hepatic Hdac expression likely plays a major role in the binge alcohol-induced hepatic steatosis and liver injury by affecting lipogenesis and fatty acid β-oxidation.

Original languageEnglish (US)
Pages (from-to)1578-1586
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume36
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Binge ethanol exposure
  • Histone deacetylases
  • Liver steatosis and injury

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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