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Abstract: Aims: Hepatic stellate cell (HSC) activation is a key step in the hepatic fibrogenic process. Increasing evidence demonstrates the pro-fibrogenic action of leptin in rodent liver. Peroxisome proliferator-activated receptor-γ (PPARγ) is a potential molecular target for inhibition of HSC activation. Our previous study suggested that leptin markedly down-regulated PPARγ gene expression in HSCs. The aim of this study is to explore the molecular mechanisms underlying the inhibitory effect of leptin on PPARγ expression in rat HSCs in vitro. Main methods: The effects of leptin on the expression and trans-activation activity of early growth response-1 (Egr-1) are examined by using real-time PCR, Western blotting analysis, transient transfection, and electrophoretic mobility shift assay. The role of Egr-1 in PPARγ gene expression is demonstrated by co-transfection approach, Western blotting analysis and real-time PCR. Key findings: We document that leptin increases Egr-1 expression at protein and mRNA levels, and significantly stimulates Egr-1 trans-activation activity. Moreover, leptin induces the expression and activity of Egr-1 through activation of extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinase/AKT signaling (PI-3K/AKT) pathway. Further investigation reveals that Egr-1 exerts a clear inhibitory effect on the promoter activity and expression of PPARγ gene and demonstrates that Egr-1 increases the expression of HSC activation markers and promotes HSC growth. Taken together, these findings suggest that Egr-1 is involved in the inhibitory effect of leptin on PPARγ expression in rat HSCs in vitro. Significance: Our results provide novel insights into the mechanisms of leptin-induced inhibition of PPARγ expression in HSCs in vitro. [Copyright &y& Elsevier]

Abstract: Hepatic stellate cell activation is a key cellular event in the development of liver fibrosis. Recently, Delta-like homolog 1 (DLK1) protein level has been shown to increase in HSC activation and serve as a new contributor to HSC activation and liver fibrosis. Curcumin, a natural yellow polyphenol, possesses therapeutic roles in many diseases including liver fibrosis and has long been used in traditional medicine. The present study was aimed to elucidate the effect of curcumin on DLK1 expression in HSCs in vitro and in vivo, which is still unknown. Our results demonstrated that curcumin reduced DLK1 expression in culture-activated HSCs and in rat model of liver fibrosis. The inhibitory effect of curcumin on DLK1 expression may be mediated in part by interruption of Shh signaling pathway, which contributes to the promotion effect of curcumin on the expression of PPAR-gamma, a key factor in inhibiting HSC activation. Our results in this study may reveal a new mechanisms through which curcumin exerts its inhibitory effect on HSC activation and liver fibrosis. [Copyright &y& Elsevier]