Binge Alcohol–Induced Microvesicular Liver Steatosis and Injury are Associated with Down‐Regulation of Hepatic Hdac1, 7, 9, 10, 11 and Up‐Regulation of Hdac3

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 h intervals) with ethanol (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 ALT activity, and liver triglyceride accumulation. Fatty acid synthase (Fas) and carnitine palmitoyl transferase 1a (Cpt1a) expression were 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), 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 ethanol 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.

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