Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter

Abstract

BackgroundBetaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation.MethodsMale wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE−/− mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target genes expression levels and the methylation status of the PPAR alpha gene were determined.ResultsApoE−/− mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE−/− mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE−/− mice. In parallel, PPAR alpha promoter methylation level were slightly increased in ApoE−/− mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE−/− mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration.ConclusionsOur findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.

Increased fatty acid β‐oxidation as a possible mechanism for fat‐reducing effect of betaine in broilers

“…In this study, 1000 mg/kg of betaine supplementation increased the PPARα mRNA expression in liver of broilers, which was similar to the results of Wang et al . (), who found that betaine improved PPARα gene expression in liver of mice. It can be partly explained by the fact that betaine acts as a methyl donor and dietary betaine levels can affect DNA methylation, leading to altered gene expression (Xing et al .…”

Choline supplementation restores substrate balance and alleviates complications of Pcyt2 deficiency

“…For example, betaine supplementation up-regulates expression of PPARα and its target genes and alleviates hepatic TAG accumulation [31]. Choline supplementation regulates the expression of genes involved in cholesterol metabolism and prevents liver damage [32].…”

Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes

“…The hepatic BHMT pathway has wide metabolic ramifications, including methylation status and lipid handling (29 ), as well as insulin and energy homeostasis (30 ). A potential interplay between betaine status, BHMT activity and transcription, and expression of the nuclear transcription factor peroxisome proliferatoractivated receptor ␣ might also affect pancreatic ␤-cells (31)(32)(33). Altered BHMT flux in the kidneys-which, in addition to the liver, harbor most of the betaine in the body (10 )-may partly explain higher urine dimethylglycine and sarcosine concentrations among patients at higher risk of T2D.…”