Changes in the expression of methionine adenosyltransferase genes and S-adenosylmethionine homeostasis during hepatic stellate cell activation

Authors

  • Komal Ramani,

    Corresponding author
    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Los Angeles, CA
    • Division of Gastrointestinal and Liver Diseases, HMR Bldg., 413, Department of Medicine, Keck School of Medicine USC, 2011 Zonal Ave., Los Angeles, CA, 90033
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    • fax: (323) 442-3234

  • Heping Yang,

    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Los Angeles, CA
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  • John Kuhlenkamp,

    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Los Angeles, CA
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  • Lauda Tomasi,

    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Los Angeles, CA
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  • Hidekazu Tsukamoto,

    1. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine University of Southern California, Los Angeles, CA
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  • José M. Mato,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepαticas y Digestivas (Ciberehd), Technology, Bizkaia, Spain
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  • Shelly C. Lu

    Corresponding author
    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Los Angeles, CA
    2. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine University of Southern California, Los Angeles, CA
    • Division of Gastrointestinal and Liver Diseases, HMR Bldg., 415, Department of Medicine, Keck School of Medicine USC, 2011 Zonal Ave., Los Angeles, CA, 90033
    Search for more papers by this author
    • fax: (323) 442-3234


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Methionine adenosyltransferase (MAT) catalyzes biosynthesis of S-adenosylmethionine (SAMe), the principle methyl donor. SAMe metabolism generates two methylation inhibitors, methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH). Liver cell proliferation is associated with induction of two nonliver-specific MATs: MAT2A, which encodes the catalytic subunit α2, and MAT2β, which encodes a regulatory subunit β that modulates the activity of the MAT2A-encoded isoenzyme MATII. We reported that MAT2A and MAT2β genes are required for liver cancer cell growth that is induced by the profibrogenic factor leptin. Also, MAT2β regulates leptin signaling. The strong association of MAT genes with proliferation and leptin signaling in liver cells led us to examine the role of these genes during HSC activation. MAT2A and MAT2β are induced in culture-activated primary rat HSCs and HSCs from 10-day bile duct ligated (BDL) rat livers. HSC activation led to a decline in intracellular SAMe and MTA levels, a drop in the SAMe/SAH ratio, and global DNA hypomethylation. The decrease in SAMe levels was associated with lower MATII activity during activation. MAT2A silencing in primary HSCs and MAT2A or MAT2β silencing in the human stellate cell line LX-2 resulted in decreased collagen and alpha-smooth muscle actin (α-SMA) expression and cell growth and increased apoptosis. MAT2A knockdown decreased intracellular SAMe levels in LX-2 cells. Activation of extracellular signal-regulated kinase and phosphatidylinositol-3-kinase signaling in LX-2 cells required the expression of MAT2β but not that of MAT2A. Conclusion: MAT2A and MAT2β genes are induced during HSC activation and are essential for this process. The SAMe level falls, resulting in global DNA hypomethylation. (HEPATOLOGY 2010.)

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