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Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase

Authors

  • Laura Gomez-Santos,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
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  • Zigmund Luka,

    1. Department of Biochemistry, Vanderbilt University, Nashville, TN
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  • Conrad Wagner,

    1. Department of Biochemistry, Vanderbilt University, Nashville, TN
    2. Tennessee Valley Department of Medical Affairs Medical Center, Nashville, TN
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  • Sara Fernandez-Alvarez,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
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  • Shelly C. Lu,

    1. Division of Gastrointestinal and Liver Diseases, USC Research Center for Liver Diseases, 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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  • Jose M. Mato,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
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  • Maria L. Martinez-Chantar,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
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  • Naiara Beraza

    Corresponding author
    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
    • Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain
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    • fax: 0034944061301


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from Instituto de Salud Carlos III (to N.B.; FIS, PS09/02010; Ministry of Health, Spain), NIH AT-1576 (to S.C.L., M.L.M.-C., and J.M.M.), Plan Nacional SAF2011-29851 to JMM, ETORTEK-2010 (to M.L.M.-C), Sanidad Gobierno Vasco 2008 (to M.L.M.-C), Educación Gobierno Vasco 2011 (to M.L.M.-C), PI11/01588 (to M.L.M.-C). Ciberehd is funded by the Instituto de Salud Carlos III. N.B. is funded by the Program Ramón y Cajal (Ministry of Science and Innovation, Spain).

Abstract

Glycine N-methyltransferase (GNMT) catabolizes S-adenosylmethionine (SAMe), the main methyl donor of the body. Patients with cirrhosis show attenuated GNMT expression, which is absent in hepatocellular carcinoma (HCC) samples. GNMT−/− mice develop spontaneous steatosis that progresses to steatohepatitis, cirrhosis, and HCC. The liver is highly enriched with innate immune cells and plays a key role in the body's host defense and in the regulation of inflammation. Chronic inflammation is the major hallmark of nonalcoholic steatohepatitis (NASH) progression. The aim of our study was to uncover the molecular mechanisms leading to liver chronic inflammation in the absence of GNMT, focusing on the implication of natural killer (NK) / natural killer T (NKT) cells. We found increased expression of T helper (Th)1- over Th2-related cytokines, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-R2/DR5, and several ligands of NK cells in GNMT−/− livers. Interestingly, NK cells from GNMT−/− mice were spontaneously activated, expressed more TRAIL, and had strong cytotoxic activity, suggesting their contribution to the proinflammatory environment in the liver. Accordingly, NK cells mediated hypersensitivity to concanavalin A (ConA)-mediated hepatitis in GNMT−/− mice. Moreover, GNMT−/− mice were hypersensitive to endotoxin-mediated liver injury. NK cell depletion and adoptive transfer of TRAIL−/− liver-NK cells protected the liver against lipopolysaccharide (LPS) liver damage. Conclusion: Our data allow us to conclude that TRAIL-producing NK cells actively contribute to promote a proinflammatory environment at early stages of fatty liver disease, suggesting that this cell compartment may contribute to the progression of NASH. (HEPATOLOGY 2012)

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