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Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide

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Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide

dc.contributor.author	Varela-Rey, Marta	es_ES
dc.contributor.author	Martínez-López, Nuria	es_ES
dc.contributor.author	Fernández-Ramos, David	es_ES
dc.contributor.author	Embade, Nieves	es_ES
dc.contributor.author	Calvisi, Diego F.	es_ES
dc.contributor.author	Woodhoo, Aswhin	es_ES
dc.contributor.author	Rodríguez, Juan	es_ES
dc.contributor.author	Fraga, Mario F.	es_ES
dc.contributor.author	Julve, Josep	es_ES
dc.contributor.author	Rodríguez-Millán, Elisabeth	es_ES
dc.contributor.author	Frades, Itziar	es_ES
dc.contributor.author	Torres, Luís	es_ES
dc.contributor.author	Luka, Zigmund	es_ES
dc.contributor.author	Wagner, Conrad	es_ES
dc.contributor.author	Esteller Badosa, Manel	es_ES
dc.contributor.author	Lu, Shelly C	es_ES
dc.contributor.author	Martínez Chantar, María	es_ES
dc.contributor.author	Mato, José M.	es_ES
dc.date.accessioned	2015-06-29T10:32:26Z
dc.date.available	2015-06-29T10:32:26Z
dc.date.issued	2010	es_ES
dc.identifier.citation	Vol. 52 Issue 1: pp. 105-114	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44788
dc.description.abstract	Deletion of glycine N-methyltransferase (GNMT) in mice, the main gene involved in liver S-adenosylmethionine (SAMe) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis. To demonstrate that the excess of hepatic SAMe is the main agent contributing to liver disease in GNMT-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 SAMe content, prevented DNA-hypermethylation and normalized the expression of critical genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More important, 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 there are subjects with GNMT mutations who have spontaneous liver disease, the clinical implication of the present findings is obvious at least with respect to these latter individuals. Especially since 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.ConclusionsThese results indicate that the anomalous accumulation of SAMe 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, and to the reversion of the appearance of the pathologic phenotype.	es_ES
dc.subject	S-Adenosylmethionine	es_ES
dc.subject	DNA methylation	es_ES
dc.subject	Ras signaling	es_ES
dc.subject	JAK/STAT signaling	es_ES
dc.subject	hepatocytes	es_ES
dc.title	Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1002/hep.23639	es_ES
dc.identifier.idgrec	060182	es_ES