Leptin reduces microRNA-122 level in hepatic stellate cells in vitro and in vivo.

Obese patients, often accompanied by hyperleptinemia, are more likely to develop liver fibrosis. Leptin, an adipocyte-derived hormone, augments inflammatory in liver and promotes hepatic stellate cell (HSC) activation (a key step for liver fibrogenesis) and liver fibrosis. microRNA-122 (miR-122) is the most abundant liver-specific miRNA and can attenuate liver fibrosis. This study examined the effect of leptin on miR-122 level in HSCs in vivo and in vitro. Results demonstrated that leptin reduced the levels of both miR-122 (mature miR-122) and primary miR-122 (pri-miR-122). The effects of leptin on the levels of miR-122 and pri-miR-122 were through at least hedgehog pathway. Leptin-induced decrease in sterol regulatory element-binding protein-1c (SREBP-1c) has been shown to contribute to leptin-induced HSC activation. We revealed a mutual promotional effect between SREBP-1c and miR-122. Further experiments indicated that miR-122 inhibited leptin-induced liver fibrosis in leptin-deficient mouse model. These data have potential implications for clarifying the mechanisms of hepatic fibrogenesis associated with elevated leptin level in human such as obese patients.

Zhai X ，Cheng F ，Ji L ，Zhu X ，Cao Q ，Zhang Y ，Jia X ，Zhou Q ，Guan W ，Zhou Y ... -  《-》

Leptin up-regulates microRNA-27a/b-3p level in hepatic stellate cells.

Obese patients, often accompanied by hyperleptinemia, are prone to liver fibrogenesis. Leptin is an adipocyte-derived hormone and plays a promotion role in liver fibrosis. Sterol regulatory element binding protein-1c (SREBP1c) exerts a crucial role in inhibiting hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Our previous studies indicated that leptin inhibited SREBP1c expression, contributing to leptin-induced HSC activation and liver fibrosis. microRNAs (miR) have emerged as important layers of regulatory control and regulate gene expression, and are implicated in numerous diseases. The present study revealed leptin up-regulation of miR-27a/b-3p levels in HSCs in vitro and in vivo. Three signaling pathways were required for leptin regulation of miR-27a/b-3p levels. miR-27a/b-3p could reduce SREBP1c and liver x receptor α (LXRα) levels, increased α-smooth muscle actin (α-SMA, a marker for HSC activation) and α1(I)collagen levels in cultured HSCs. miR-27a/b-3p regulation of SREBP1c and LXRα were independent of 3'-untranslated region of SREBP1c and LXRα mRNA. In vivo experiments further demonstrated the miR-27a/b-3p involved in leptin-associated decrease in SREBP1 level in HSCs, HSC activation, and liver fibrosis. These data might have potential implications for our understanding of molecular mechanisms underlying leptin roles in liver fibrogenesis of obese patients with hyperleptinaemia.

Li Z ，Ji L ，Su S ，Zhu X ，Cheng F ，Jia X ，Zhou Q ，Zhou Y ... -  《-》

Stat3 pathway correlates with the roles of leptin in mouse liver fibrosis and sterol regulatory element binding protein-1c expression of rat hepatic stellate cells.

Leptin, the adipocyte-derived hormone, plays an unique role in promoting liver fibrosis. Hepatic stellate cell (HSC) activation is the key step in liver fibrogenesis and sterol regulatory element binding protein-1c (SREBP-1c, a pivotal transcription factor for adipocyte differentiation) exerts a critical function in inhibition of HSC activation. Stat3 pathway is the main pathway induced by leptin and its role in liver fibrogenesis is controversial. Our previous results demonstrated the inhibitory effect of leptin on SREBP-1c expression in HSCs. The present study aimed to explore the role of Stat3 pathway in leptin-induced liver fibrogenesis in mouse model, focusing on examining the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs in vitro and in vivo. Results suggested that Stat3 pathway mediated the promotional role of leptin in liver fibrosis in mouse and was involved in leptin inhibition of SREBP-1c expression in HSCs. Leptin-induced Stat3 activation was, at least partially, ERK pathway-dependent in cultured HSCs and was correlated positively with β-catenin activity and negatively with liver X receptor α expression and activity which influenced SREBP-1c expression in HSCs. The decrease in SREBP-1c expression by leptin-induced Stat3 pathway led to the increase in the marker for HSC activation and in α1(I) collagen expression in HSCs. In summary, the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs might contribute to the role of leptin in liver fibrosis in mouse, thus advancing understanding of the mechanisms of liver fibrogenesis associated with leptin.

Zhang W ，Niu M ，Yan K ，Zhai X ，Zhou Q ，Zhang L ，Zhou Y ... -  《-》

Leptin suppresses microRNA-122 promoter activity by phosphorylation of foxO1 in hepatic stellate cell contributing to leptin promotion of mouse liver fibrosis.

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.

Cao Q ，Zhu X ，Zhai X ，Ji L ，Cheng F ，Zhu Y ，Yu P ，Zhou Y ... -  《-》

The β-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis.

Liver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element-binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the β-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis. HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays. Leptin increased β-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3β at Ser(9) and subsequent stabilization of β-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced β-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor α. In a mouse model of liver injury, the β-catenin pathway was shown to be involved in leptin-induced liver fibrosis. The β-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels.

Zhai X ，Yan K ，Fan J ，Niu M ，Zhou Q ，Zhou Y ，Chen H ，Zhou Y ... -  《-》