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.

Exendin-4 regulates redox homeostasis in rats fed with high-fat diet

“…However, the underlying mechanism remains largely unknown. In this study, our results are consistent with these observations that elevation of plasma homocysteine level is due to the down-regulation of CBS in the livers of hyperlipidemic rats [15,26]. Our results suggest that HFD suppresses the protein expression of CBS probably by inducing rno-miR-376c in rats.…”

Choline supplementation restores substrate balance and alleviates complications of Pcyt2 deficiency

“…The increased FA β-oxidation was also demonstrated by activation of AMPK/ACC pathway by choline supplementation. AMPK stimulation of FA β-oxidation was also shown after methyl group supplementation in obese mice [21]. Altogether, the major metabolic changes caused by choline supplementation were the positive effects on TAG and FA mitochondrial metabolism.…”

“…A previous study has shown that methyl group supplementation, including choline, betaine, folic acid, vitamin B12 and methionine, could reduce fat accumulation in the liver of obese mice induced by high-fat diet [21]. We proposed that stimulation of choline metabolism could be a good strategy to reverse the metabolic complications of Pcyt2 deficiency.…”

Neohesperidin Exerts Lipid-Regulating Effects in vitro and in vivo via Fibroblast Growth Factor 21 and AMP-Activated Protein Kinase/Sirtuin Type 1/Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1α Signaling Axis

“…Since the AMPK-SIRT1-PGC-1α axis was reported mediating FGF21 signaling in adipocyte and liver [22,41], we hypothesized that an increased FGF21 induced by NHP might activate the AMPK-SIRT1-PGC-1α pathway. AMPK, as energy sensor, plays an important role in regulating glucose and lipid metabolism [19,20,21]. The activation of AMPK by NHP and the elimination of TG-lowering effect of NHP, with siRNA targeting AMPK or using compound C as an inhibitor of AMPK, indicated that NHP might attenuate lipid accumulation of AMPK.…”

“…Several studies have demonstrated that FGF21 can lower plasma lipids and ameliorate obesity-associated dyslipidemia [15,16,17,18]. As a cellular energy sensor, AMP-activated protein kinase (AMPK) not only integrates diverse physiological signals to restore energy balance among activities, but also plays an important role in lipid metabolism [19,20,21], and recent researches reported that AMPK pathway could be activated by FGF21 [22]. However, the specific role of FGF21 and AMPK in regulating lipid metabolism of NHP remained unknown.…”