HDAC1 overexpression promoted by METTL3-IGF2BP2 inhibits FGF21 expression in metabolic syndrome-related liver injury

Metabolic syndrome (MetS) represents a cluster of diseases that include diabetes and insulin resistance. A combination of these metabolic disorders damages liver function. We hypothesized here that HDAC1 inhibits FGF21 expression through histone deacetylation, thereby accentuating liver injury in rats with MetS. MetS rats induced by a high-fat diet were monitored weekly for blood pressure and body weight. The changes of hepatic injury parameters were also measured. The pathological changes in the liver were observed by HE staining and oil red O staining. We found that HDAC1 was increased in the liver of rats with MetS, while sh-HDAC1 reduced blood pressure, body weight and hepatic injury parameters. Improvement of structural pathological alterations and reduction of lipid deposition were observed after HDAC1 inhibition. Notably, HDAC1 inhibited FGF21 expression through histone deacetylation. The hepatoprotective effects of sh-HDAC1 on rats were reversed by adenovirus-mediated knockdown of FGF21. Moreover, METTL3 mediated the m6A modification of HDAC1 mRNA and increased its binding to IGF2BP2. Consistently, sh-METTL3 inhibited HDAC1 and increased FGF21 expression, thereby ameliorating liver injury in MetS rats. This study discovered that HDAC1 is capable of managing liver injury in MetS. Targeting HDAC1 may be an optimal treatment for MetS-related liver injury.