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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]

Aims Peroxisome-proliferator activated receptor γ (PPARγ) plays a pivotal role in inhibition of hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis. Adipocyte-derived hormone leptin has been shown to promote liver fibrosis in murine and human. PPARγ includes two subtypes, PPARγ1 and PPARγ2. Our previous study indicated that leptin down-regulated PPARγ1 expression in HSCs. The aim of this study was to investigate the effect of leptin on PPARγ2 expression and the underlying mechanisms in HSCs. Main methods Real-time PCR and western blot analyses were used to examine gene expression. The promoter activities were detected by luciferase assay. Key findings Leptin reduced PPARγ2 expressions at promoter level, mRNA level, and protein level in HSCs, which required β-catenin, p38 mitogen-activated protein kinase, and delta-like homolog1 (DLK1) signaling pathways. Leptin induced GATA binding protein 2 (GATA2) expression through DLK1 pathway and GATA2 reduced PPARγ2 expression. Ectopic expression of PPARγ2 reduced the protein levels of α-smooth muscle actin and α1(I)collagen in HSCs. Significance Since obese patients, often accompanied by hyperleptinemia, are more prone to liver fibrosis, the data from this study might have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinemia. [ABSTRACT FROM AUTHOR]