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Impaired S‐adenosylmethionine metabolism inhibits IFNα‐mediated anti‐HCV gene expression
Author(s) -
Mathews Stephanie,
JoshiBarve Swati,
McClain Craig,
Barve Shirish
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1090.9
Subject(s) - hepatitis c virus , isg15 , interferon , hepatitis c , interferon stimulated gene , drug metabolism , ribavirin , metabolism , biology , virology , pharmacology , virus , medicine , immunology , gene , endocrinology , biochemistry , immune system , ubiquitin , innate immune system
Hepatitis C virus (HCV) is a major cause of chronic liver disease, which is a huge burden on the United States healthcare system. The FDA‐approved standard of treatment is pegylated interferon‐alpha (IFNα) in combination with ribavirin; however up to 50% of patients do not respond to this therapy. S‐adenosylmethionine (SAM) is the major methyl donor in cellular metabolic reactions and impaired SAM metabolism is a well documented feature of chronic liver injury. The present work was carried out to examine the impact of impaired SAM metabolism on the expression of IFNα‐stimulated anti‐HCV genes. SAM metabolism was impaired in human hepatoma cells by the pharmacologic inhibition of S‐adenosylhomocysteine hydrolase (SAHH) leading to an increase in SAH, which significantly decreased methylation potential by decreasing SAM/SAH ratio. Impaired SAM metabolism was observed to significantly inhibit IFNα‐inducible anti‐HCV gene expression, including PKR, OAS, and ISG15. Importantly, impaired SAM metabolism hindered the ability of IFNα to suppress viral RNA replication in an HCV replicon cell line, as analyzed by real‐time PCR. These data reveal the importance of SAM metabolism in managing HCV infection by the current IFNα treatment regimen and also suggest the use of SAM as adjunct therapy.