- 作者：Shabnam Pooya ; S¨¦bastien Blaise ; Maira Moreno Garcia ; Jean Giudicelli ; Jean-Marc Alberto ; Rosa-Maria Gu¨¦ant-Rodriguez ; Elise Jeannesson ; Naig Gueguen ; Aude Bressenot ; B¨¦n¨¦dicte Nicolas ; Yves Malthiery ; Jean-Luc Daval ; Laurent Peyrin-Biroulet ; Jean-Pierre Bronowicki ; Jean-Louis Gu¨¦ant
- 关键词：ACC ; acetyl-CoA carboxylase ; ADMA ; asymmetric dimethylarginine ; AFU ; arbitrary fluorescence units ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; BHMT ; betaine&ndash ; homocysteine methyltransferase ; CBS ; cystathionine ß ; -synthase ; CO
- 刊名：Journal of Hepatology
- 出版年：2012
- 出版时间：August, 2012
- 年：2012
- 卷：57
- 期：2
- 页码：344-351
- 全文大小：1551 K
Background & Aims
Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown.Methods
We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation.
Results
The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-l-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-¦Á, ERR-¦Á and HNF-4¦Á, and hypomethylation of PGC-1¦Á co-activator that reduced its binding with PPAR-¦Á, ERR-¦Á, and HNF-4¦Á.
Conclusions
The liver steatosis resulted predominantly from hypomethylation of PGC1-¦Á, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis.