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

Authors

  • Irina Kirpich,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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    • The first two authors contributed equally.
  • Smita Ghare,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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    • The first two authors contributed equally.
  • Jingwen Zhang,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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  • Leila Gobejishvili,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center, Louisville, Kentucky
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  • Giorgi Kharebava,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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  • Swati Joshi Barve,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center, Louisville, Kentucky
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  • David Barker,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center, Louisville, Kentucky
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  • Akshata Moghe,

    1. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
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  • Craig J. McClain,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center, Louisville, Kentucky
    3. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
    4. Robley Rex Veterans Medical Center, Louisville, Kentucky
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  • Shirish Barve

    Corresponding author
    1. University of Louisville Alcohol Research Center, Louisville, Kentucky
    2. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
    • Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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Reprint requests: Shirish Barve, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, 505 South Hancock str. CTR, Louisville, KY 40202. Tel.: 502-852-5245; Fax: 502-852-6904; E-mail: shirishbarve@gmail.com

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.

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