LAUSR

&NA; Adipocytokine leptin promotes hepatic stellate cell (HSC) activation (a key step in liver fibrogenesis) and liver fibrosis. microRNA‐122 (miR‐122) is the most abundant liver‐specific miRNA and was demonstrated to inhibit liver fibrosis and reduced HSC proliferation. Our previous study revealed that leptin reduced miR‐122 level in HSCs. This study was aimed to investigate whether leptin affected miR‐122 promoter and the underlying mechanisms in HSCs. Results showed that leptin inhibited miR‐122 promoter activity. Forkhead box protein O1(FoxO1) bound to miR‐122 promoter at a site around – 56 and thus promoted miR‐122 promoter activity, which could be suppressed by leptin‐induced phosphorylation of FoxO1 at serine 256. The PI3K/Akt signaling pathway was involved in leptin‐induced phosphorylation of FoxO1 and the effect of leptin on miR‐122 expression. Furthermore, FoxO1 increased miR‐122 and pri‐miR‐122 (primary miR‐122) levels in HSCs in vivo, and reduced leptin‐induced HSC activation and liver fibrosis in ob/ob mouse (leptin deficient) model. In conclusion, leptin suppressed microRNA‐122 expression by PI3K/Akt/foxO1 axis in HSCs. These results have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinaemia. Graphical abstract Figure. No caption available. HighlightsLeptin inhibits miR‐122 promoter activity in hepatic stellate cells (HSCs).FoxO1 binds to miR‐122 promoter and promotes miR‐122 promoter activity.PI3K/Akt mediates the effects of leptin on FoxO1 phosphorylation and miR‐122 levels.FoxO1 increases miR‐122 level and reduces leptin roles in HSC and liver fibrosis.