Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver.

Abstract

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-α, ERR-α and HNF-4α, and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α, and HNF-4α.

CONCLUSIONS:

The liver steatosis resulted predominantly from hypomethylation of PGC1-α, 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.

• Authors: Shabnam Pooya, Sébastien Blaise, Maira Moreno Garcia, Jean Giudicelli, Jean-Marc Alberto, Rosa-Maria Guéant-Rodriguez, Elise Jeannesson, Naig Gueguen, Aude Bressenot, Bénédicte Nicolas, Yves Malthiery, Jean-Luc Daval, Laurent Peyrin-Biroulet, Jean-Pierre Bronowicki, Jean-Louis Guéant
• Journal: Journal of hepatology (J Hepatol) Vol. 57 Issue 2 Pg. 344-51 (Aug 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22521344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Estrogen Receptor alpha
• Fatty Acids
• Hepatocyte Nuclear Factor 4
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• RNA-Binding Proteins
• Receptors, Estrogen
• Transcription Factors
• Folic Acid
• Vitamin B 12

Topics

• Animals
• Electron Transport
• Endoplasmic Reticulum Stress
• Energy Metabolism
• Estrogen Receptor alpha (analysis, physiology)
• Fatty Acids (metabolism)
• Fatty Liver (etiology)
• Folic Acid (blood)
• Hepatocyte Nuclear Factor 4 (analysis, physiology)
• Liver (metabolism)
• Methylation
• Oxidation-Reduction
• Oxidative Stress
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA-Binding Proteins (metabolism)
• Rats
• Rats, Wistar
• Receptors, Estrogen (analysis, physiology)
• Transcription Factors (metabolism)
• Vitamin B 12 (blood)
• ERRalpha Estrogen-Related Receptor