Effect of methionine-deficient and methionine-supplemented diets on the hepatic one-carbon and lipid metabolism in mice.
METHODS
A compromised nutritional status in methyl-group donors may provoke several molecular alterations triggering the development of nonalcoholic fatty liver disease (NAFLD) in humans and experimental animals. In this study, we investigated a role and the underlying molecular mechanisms of methionine metabolic pathway malfunctions in the pathogenesis of NAFLD.


RESULTS
We fed female Swiss albino mice a control (methionine-adequate) diet and two experimental (methionine-deficient or methionine-supplemented) diets for 10 weeks, and the levels of one-carbon metabolites, expression of one-carbon and lipid metabolism genes in the livers were evaluated. We demonstrate that both experimental diets increased hepatic levels of S-adenosyl-l-homocysteine and homocysteine, altered expression of one-carbon and lipid metabolism genes, and caused lipid accumulation, especially in mice fed the methionine-deficient diet. Markers of oxidative and ER stress response were also elevated in the livers of mice fed either diet.


CONCLUSIONS
Our findings indicate that both dietary methionine deficiency and methionine supplementation can induce molecular abnormalities in the liver associated with the development of NAFLD, including deregulation in lipid and one-carbon metabolic pathways, and induction of oxidative and ER stress. These pathophysiological events may ultimately lead to lipid accumulation in the livers, triggering the development of NAFLD.
Department of Genetic, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Alexandre Ferro
AF
Aissa
Volodymyr
V
Tryndyak
Aline
A
de Conti
Stepan
S
Melnyk
Tarsila Daysy Ursula Hermogenes
TD
Gomes
Maria Lourdes Pires
ML
Bianchi
S Jill
SJ
James
Frederick A
FA
Beland
Lusania Maria Greggi
LM
Antunes
Igor P
IP
Pogribny
D000818:Animals; D019587:Dietary Supplements; D005260:Female; D005978:Glutathione / Q000097:blood; D006710:Homocysteine / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage* / Q000172:deficiency*; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy; D014280:Triglycerides / Q000097:blood
D014280:Triglycerides; D006710:Homocysteine; D008715:Methionine; D005978:Glutathione
Fatty liver; Homocysteine; Methionine-deficiency; Methionine-supplementation; Mice; Oxidative stress