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

Marta Varela-Rey, Nuria Martínez-López, David Fernández-Ramos, Nieves Embade, Diego F. Calvisi, Aswhin Woodhoo, Juan Rodríguez, Mario F. Fraga, Josep Julve, Elisabeth Rodríguez-Millán, Itziar Frades, Luís Torres, Zigmund Luka, Conrad Wagner, Manel Esteller, Shelly C. Lu, M. Luz Martínez-Chantar, José M. Mato

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 GNMTmutations. 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.

Original languageEnglish (US)
Pages (from-to)105-114
Number of pages10
JournalHepatology
Volume52
Issue number1
DOIs
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Glycine N-Methyltransferase
Niacinamide
Fatty Liver
Knockout Mice
Liver Cirrhosis
S-Adenosylmethionine
Liver
Nicotinamide N-Methyltransferase
Liver Diseases
Oxidative Stress
Fatty Acids
Pellagra
Cell Proliferation
Apoptosis
Inflammation
Gene Expression
Fibrosis
Phenotype
Mutation

ASJC Scopus subject areas

  • Hepatology

Cite this

Varela-Rey, M., Martínez-López, N., Fernández-Ramos, D., Embade, N., Calvisi, D. F., Woodhoo, A., ... Mato, J. M. (2010). Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide. Hepatology, 52(1), 105-114. https://doi.org/10.1002/hep.23639

Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide. / Varela-Rey, Marta; Martínez-López, Nuria; Fernández-Ramos, David; Embade, Nieves; Calvisi, Diego F.; Woodhoo, Aswhin; Rodríguez, Juan; Fraga, Mario F.; Julve, Josep; Rodríguez-Millán, Elisabeth; Frades, Itziar; Torres, Luís; Luka, Zigmund; Wagner, Conrad; Esteller, Manel; Lu, Shelly C.; Martínez-Chantar, M. Luz; Mato, José M.

In: Hepatology, Vol. 52, No. 1, 07.2010, p. 105-114.

Research output: Contribution to journalArticle

Varela-Rey, M, Martínez-López, N, Fernández-Ramos, D, Embade, N, Calvisi, DF, Woodhoo, A, Rodríguez, J, Fraga, MF, Julve, J, Rodríguez-Millán, E, Frades, I, Torres, L, Luka, Z, Wagner, C, Esteller, M, Lu, SC, Martínez-Chantar, ML & Mato, JM 2010, 'Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide', Hepatology, vol. 52, no. 1, pp. 105-114. https://doi.org/10.1002/hep.23639
Varela-Rey M, Martínez-López N, Fernández-Ramos D, Embade N, Calvisi DF, Woodhoo A et al. Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide. Hepatology. 2010 Jul;52(1):105-114. https://doi.org/10.1002/hep.23639
Varela-Rey, Marta ; Martínez-López, Nuria ; Fernández-Ramos, David ; Embade, Nieves ; Calvisi, Diego F. ; Woodhoo, Aswhin ; Rodríguez, Juan ; Fraga, Mario F. ; Julve, Josep ; Rodríguez-Millán, Elisabeth ; Frades, Itziar ; Torres, Luís ; Luka, Zigmund ; Wagner, Conrad ; Esteller, Manel ; Lu, Shelly C. ; Martínez-Chantar, M. Luz ; Mato, José M. / Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide. In: Hepatology. 2010 ; Vol. 52, No. 1. pp. 105-114.
@article{47cfbf8c863345fe8b89b5bade6fa0ea,
title = "Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide",
abstract = "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 GNMTmutations. 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.",
author = "Marta Varela-Rey and Nuria Mart{\'i}nez-L{\'o}pez and David Fern{\'a}ndez-Ramos and Nieves Embade and Calvisi, {Diego F.} and Aswhin Woodhoo and Juan Rodr{\'i}guez and Fraga, {Mario F.} and Josep Julve and Elisabeth Rodr{\'i}guez-Mill{\'a}n and Itziar Frades and Lu{\'i}s Torres and Zigmund Luka and Conrad Wagner and Manel Esteller and Lu, {Shelly C.} and Mart{\'i}nez-Chantar, {M. Luz} and Mato, {Jos{\'e} M.}",
year = "2010",
month = "7",
doi = "10.1002/hep.23639",
language = "English (US)",
volume = "52",
pages = "105--114",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide

AU - Varela-Rey, Marta

AU - Martínez-López, Nuria

AU - Fernández-Ramos, David

AU - Embade, Nieves

AU - Calvisi, Diego F.

AU - Woodhoo, Aswhin

AU - Rodríguez, Juan

AU - Fraga, Mario F.

AU - Julve, Josep

AU - Rodríguez-Millán, Elisabeth

AU - Frades, Itziar

AU - Torres, Luís

AU - Luka, Zigmund

AU - Wagner, Conrad

AU - Esteller, Manel

AU - Lu, Shelly C.

AU - Martínez-Chantar, M. Luz

AU - Mato, José M.

PY - 2010/7

Y1 - 2010/7

N2 - 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 GNMTmutations. 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.

AB - 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 GNMTmutations. 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.

UR - http://www.scopus.com/inward/record.url?scp=77954226432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954226432&partnerID=8YFLogxK

U2 - 10.1002/hep.23639

DO - 10.1002/hep.23639

M3 - Article

VL - 52

SP - 105

EP - 114

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 1

ER -