FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease among children and adolescents in the developed world. Betaine, as a methyl donor, recently has been demonstrated to exert its hepatoprotective effects through rectifying the genomic DNA hypomethylation state. However, whether betaine supplementation affects N6-methyladenosine (m(6)A) mRNA methylation in NAFLD is still unknown. We conducted the current study to investigate the effects of betaine supplementation during adolescence on high-fat diet-induced pathological changes in liver of mice, and we further identified the effects of betaine supplementation on expression of the fat mass and obesity-associated gene (FTO) and hepatic m(6)A mRNA methylation. Our results showed that betaine supplementation across adolescence significantly alleviated high-fat-induced impairment of liver function and morphology as well as ectopic fat accumulation. Surprisingly, no significant effects on serum TG and NEFA level, as well as fat mass, were observed in mice supplemented with betaine. We also found that high-fat diet upregulated ACC1 and FAS gene expression and downregulated HSL and ATGL gene expression. However, these alterations were rectified by betaine supplementation. Moreover, an m(6)A hypomethylation state and increased FTO expression were detected in mice fed with high-fat diet, while betaine supplementation prevented these changes. Our results suggested that betaine supplementation during adolescence could protect mice from high-fat-induced NAFLD by decreasing de novo lipogenesis and increasing lipolysis. Furthermore, a novel FTO-dependent function of m(6)A may involve in the hepatoprotective effects of betaine.

MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein

“…The modification of m 6 A needs various functional proteins and enzymes, such as the methylases mettl3/mettl14 and demethylases FTO/ALKBH5 and so on (5,7,37). YTHDF2 is an m 6 A reader protein that has important biological functions in modulation of mRNA m 6 A (38).…”

Milk’s Role as an Epigenetic Regulator in Health and Disease

“…Although genes involved in methylation were differentially regulated in skeletal muscle of FTO-4 mice, no effect of FTO overexpression on m 6 A methylation of total mRNA was detected [227]. However, an m 6 A hypomethylation state was associated with increased FTO expression in mice fed with high-fat diet, whereas the supplementation of the methyl donor betaine prevented these changes [250]. …”

Betaine chemistry, roles, and potential use in liver disease

“…It is the most common cause of liver disease in children and adolescents [59]. NAFLD includes a spectrum of abnormalities ranging from triglyceride accumulation in hepatocytes (often symptom-free) to non-alcoholic steatohepatitis (NASH).…”