Impact of Altered Methylation in Cytokine Signaling and Proteasome Function in Alcohol and Viral-Mediated Diseases

Authors

  • Kusum K. Kharbanda,

    Corresponding author
    1. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Internal Medicine, Biochemistry & Molecular Biology, Omaha, Nebraska
    • Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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  • Fawzia Bardag-Gorce,

    1. Department of Pathology, Los Angeles Biomedical Research Institute, Harbor UCLA Medical Center, Torrance, California
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  • Shirish Barve,

    1. Department of Medicine and Alcohol Research Center, University of Louisville, Louisville, Kentucky
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  • Patricia E. Molina,

    1. Department of Physiology and Alcohol and Drug Abuse Center of Excellence , Louisiana State University Health Sciences Center, New Orleans, Louisiana
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  • Natalia A. Osna

    1. Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
    2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
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  • The following critical review condenses the proceedings of a symposium at the International Society for the Biomedical Research on Alcoholism Meeting held September 13–16, 2010, in Paris, France.

Reprint requests: Kusum K. Kharbanda, PhD, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105; Tel.: 402-995-3752; Fax: 402-449-0604; E-mail: kkharbanda@unmc.edu

Abstract

Data from several laboratories have shown that ethanol (EtOH) feeding impairs many essential methylation reactions that contribute to alcoholic liver disease (ALD). EtOH is also a comorbid factor in the severity of hepatitis C virus–induced liver injury. The presence of viral proteins further exacerbates the methylation defects to disrupt multiple pathways that promote the pathogenesis of liver disease. This review is a compilation of presentations that linked the methylation reaction defects with proteasome inhibition, decreased antigen presentation, and impaired interferon (IFN) signaling in the hepatocytes and dysregulated TNFα expression in macrophages. Two therapeutic modalities, betaine and S-adenosylmethionine, can correct methylation defects to attenuate many EtOH-induced liver changes, as well as improve IFN signaling pathways, thereby overcoming viral treatment resistance.

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