title: Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels.
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 β-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 β-oxidation control, that mediates increased fatty acid utilization and thereby prevents further hepatic lipid accumulation.
authors: Biochemistry Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany ; PhD Group - Epigenetics, Imprinting and Nutrition, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Christoph
authors: C
authors: Dahlhoff
authors: Nutritional Medicine Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Stefanie
authors: S
authors: Worsch
authors: Biochemistry Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Manuela
authors: M
authors: Sailer
authors: Clinical Chemistry and Laboratory Medicine/Central Laboratory, University Hospital of the Saarland, 66421 Homburg, Germany ; Clinical Haemostasiology and Transfusion Medicine, University Hospital of the Saarland, 66421 Homburg, Germany.
authors: Björn A
authors: BA
authors: Hummel
authors: Biochemistry Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Jarlei
authors: J
authors: Fiamoncini
authors: Nutritional Medicine Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Kirsten
authors: K
authors: Uebel
authors: Clinical Chemistry and Laboratory Medicine/Central Laboratory, University Hospital of the Saarland, 66421 Homburg, Germany.
authors: Rima
authors: R
authors: Obeid
authors: Biochemistry Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Christian
authors: C
authors: Scherling
authors: Clinical Chemistry and Laboratory Medicine/Central Laboratory, University Hospital of the Saarland, 66421 Homburg, Germany.
authors: Jürgen
authors: J
authors: Geisel
authors: PhD Group - Epigenetics, Imprinting and Nutrition, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany ; Nutritional Medicine Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Bernhard L
authors: BL
authors: Bader
authors: Biochemistry Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, 85350 Freising-Weihenstephan, Germany.
authors: Hannelore
authors: H
authors: Daniel
keywords: 3-HB, β-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 β-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; β-HAD, β-hydroxyacyl CoA dehydrogenase; β-oxidation