Gene therapy targeting miR-212-3p exerts therapeutic effects on MAFLD similar to those of exercise

Exercise is the main treatment for patients with metabolic-associated fatty liver disease (MAFLD); however, it may be difficult for some patients to adhere to or tolerate an exercise regime. Thus, finding a treatment alternative to exercise is of particular importance. The authors have previously demonstrated that the high expression of microRNA (miRNA/miR)-212 promotes lipogenesis in vitro. The present study aimed to explore the therapeutic potential, as well as the mechanisms of action of miR-212 in MAFLD. The expression of miR-212-3p, but not that of miR-212-5p, was found to be significantly elevated in MAFLD and to be decreased by exercise. Compared with exercise treatment, the inhibition of miR-212-3p expression in a mouse model fed a high-fat diet exerted beneficial effects on MAFLD similar to those of exercise. Conversely, the overexpression of miR-212-3p abolished the ameliorative effects of exercise on MAFLD. Fibroblast growth factor 21 (FGF21) and chromodomain helicase DNA binding protein 1 (CHD1) were identified as target genes of miR-212-3p in lipid metabolism using bioinformatics analysis. Mechanistically, the inhibition of miR-212-3p mimicked the effects of exercise on lipid metabolism by regulating FGF21, but not CHD1. The exercise-related transcription factor, early growth response 1 (EGR1), was identified upstream of miR-212-3p through promoter motif analysis. EGR1 overexpression inhibited miR-212-3p expression. The overexpression of miR-212-3p abolished the effects of exercise on lipid metabolism by exogenously attenuating the transcriptional repression of EGR1. Moreover, the overexpression of miR-212-3p abolished the regulatory effects of EGR1 on FGF21. On the whole, the present study demonstrates that miR-212-3p plays a key role in the effects of exercise on MAFLD. The findings presented herein suggest a potential therapeutic effect of targeting miR-212-3p in MAFLD.