Vitamin D alleviates HFD-induced hepatic fibrosis by inhibiting DNMT1 to affect the TGFβ1/Smad3 pathway

Increasing evidence points toward vitamin D (VD) having lipometabolism and immune-related properties to protect against related metabolic diseases through influencing DNA methylation with inconsistent results. Simultaneously, its relatively precise molecular metabolism on the progression of metabolic-associated fatty liver disease (MAFLD) remains uncertain. Here, we report an unprecedented role and possible mechanism for VD supplementation on the alleviation of high-fat diet (HFD)-induced MAFLD. Over time, our results demonstrated that metabolic disorders in the HFD-induced MAFLD were aggravated with a certain time-response dependence and accompanied by reduced VD metabolites. All these could be alleviated under sufficient VD supplementation <i>in vivo</i> and vitro. It was partially by inhibiting the expressions of DNMT1 to reverse the epigenetic patterns on the VD metabolism genes and TGFβR1, which ultimately triggered the TGFβ1/Smad3 pathway to result in the development of MAFLD. Furthermore, the protective effects of VD were weakened by the treatment with gene silencing of DNMT1.