Fatty Liver and Fibrosis in Glycine N-Methyltransferase Knockout Mice Is Prevented by Nicotinamide
Por:
Varela-Rey, M, Martinez-Lopez, N, Fernandez-Ramos, D, Embade, N, Calvisi, DF, Woodhoo, A, Rodriguez, J, Fraga, MF, Julve, J, Rodriguez-Millan, E, Frades, I, Torres, L, Luka, Z, Wagner, C, Esteller, M, Lu, SC, Martinez-Chantar, ML, Mato, JM
Publicada:
1 jul 2010
Resumen:
Deletion of glycine N-methyltransferase (GNMT), the main gene involved in liver S-adenosylmethionine (SAM) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis in mice. To demonstrate that the excess of hepatic SAM is the main agent contributing to liver disease in GNMT knockout (KO) mice, we treated 1.5-month-old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase. NAM administration markedly reduced hepatic SAM content, prevented DNA hypermethylation, and normalized the expression of critical genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More importantly, NAM treatment prevented the development of fatty liver and fibrosis in GNMT-KO mice. Because GNMT expression is down-regulated in patients with cirrhosis, and because some subjects with GNMT mutations have spontaneous liver disease, the clinical implications of the present findings are obvious, at least with respect to these latter individuals. Because NAM has been used for many years to treat a broad spectrum of diseases (including pellagra and diabetes) without significant side effects, it should be considered in subjects with GNMT mutations. Conclusion: The findings of this study indicate that the anomalous accumulation of SAM in GNMT-KO mice can be corrected by NAM treatment leading to the normalization of the expression of many genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis, as well as reversion of the appearance of the pathologic phenotype. (HEPATOLOGY 2010;52:105-114)
Filiaciones:
Varela-Rey, M:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Martinez-Lopez, N:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Fernandez-Ramos, D:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Embade, N:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Calvisi, DF:
Ernst Moritz Arndt Univ Greifswald, Inst Pathol, Greifswald, Germany
Woodhoo, A:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Rodriguez, J:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Fraga, MF:
CSIC, CNB, Dept Immunol & Oncol, Madrid, Spain
Julve, J:
Hosp Santa Creu & Sant Pau, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Inst Recerca, Barcelona, Spain
Rodriguez-Millan, E:
Hosp Santa Creu & Sant Pau, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Inst Recerca, Barcelona, Spain
Frades, I:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Torres, L:
Univ Valencia, Dept Bioquim & Biol Mol, E-46003 Valencia, Spain
Luka, Z:
Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA
Wagner, C:
Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA
Esteller, M:
Belvitge Biomed Res Inst, Canc Epigenet & Biol Program, Barcelona, Catalonia, Spain
Lu, SC:
Univ So Calif, Keck Sch Med, Div Gastroenterol & Liver Dis, Res Ctr Liver Dis, Los Angeles, CA 90033 USA
Martinez-Chantar, ML:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Mato, JM:
CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain
Green Accepted
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