Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels.
Mol Metab
; 3(5): 565-80, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-25061561
ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic lipid accumulation and steatosis, and is closely linked to liver one-carbon (C1) metabolism. We assessed in C57BL6/N mice whether NAFLD induced by a high-fat (HF) diet over 8 weeks can be reversed by additional 4 weeks of a dietary methyl-donor supplementation (MDS). MDS in the obese mice failed to reverse NAFLD, but prevented the progression of hepatic steatosis associated with major changes in key hepatic C1-metabolites, e.g. S-adenosyl-methionine and S-adenosyl-homocysteine. Increased phosphorylation of AMPK-α together with enhanced ß-HAD activity suggested an increased flux through fatty acid oxidation pathways. This was supported by concomitantly decreased hepatic free fatty acid and acyl-carnitines levels. Although HF diet changed the hepatic phospholipid pattern, MDS did not. Our findings suggest that dietary methyl-donors activate AMPK, a key enzyme in fatty acid ß-oxidation control, that mediates increased fatty acid utilization and thereby prevents further hepatic lipid accumulation.
3-HB, ß-hydroxybutyrate; ACC, acetyl-CoA carboxylase; AMP-activated protein kinase; AMPK, AMP-activated protein kinase; ANT, adenine nucleotide translocase; Acyl-carnitines; Bhmt, betaine-homocysteine methyltransferase; C, control diet; C1, one-carbon; CACT, carnitine-acylcarnitine transporter; CMS, methyl-donor supplemented control diet; Cbs, cystathionine ß-synthase; Cpt1a, carnitine palmitoyltransferase-1a; DIO, diet-induced obesity; Fasn, fatty acid synthase; GNMT, glycine N-methyltransferase; Gapdh, glyceraldehyde 3-phosphate dehydrogenase; HF, high-fat diet; HFMS, methyl-donor supplemented high-fat diet; HMW adiponectin, high molecular weight adiponectin; HSP90, heat shock protein 90; Hcy, homocysteine; Hepatic steatosis; Hprt1, hypoxanthine phosphoribosyltransferase 1; LDL, low density lipoprotein; MAT, methionine adenosyltransferase; MCD, malonyl-CoA decarboxylase; MDS, methyl-donor supplementation; MTR, methionine synthase; NAFLD, non-alcoholic fatty liver disease; NEFA, non-esterified fatty acids; Obesity; One-carbon metabolism; PC, phosphatidylcholine; PGC1α, peroxisome proliferator-activated receptor-γ co-activator-1α; PL, phospholipids; PPARα, peroxisome proliferator-activated receptor-α; Pemt, phosphatidylethanolamine methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SM, sphingomyelin; SREBP1c, sterol regulatory element-binding protein-1c; TG, triacylglycerol; VAT, visceral adipose tissue; VLDL, very low density lipoprotein; ß-HAD, ß-hydroxyacyl CoA dehydrogenase; ß-oxidation
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Base de dados:
MEDLINE
Idioma:
En
Revista:
Mol Metab
Ano de publicação:
2014
Tipo de documento:
Article