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  • Title: Leptin stimulates alpha1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway.
    Author: Niu L, Wang X, Li J, Huang Y, Yang Z, Chen F, Ni H, Jin Y, Lu X, Cao Q.
    Journal: Liver Int; 2007 Nov; 27(9):1265-72. PubMed ID: 17919239.
    Abstract:
    BACKGROUND/AIMS: Leptin has been recognized as a profibrogenic hormone in the liver and is involved in collagen type I formation by activated hepatic stellate cells (HSCs) in response to fibrogenic substances, but the molecular signal mechanisms by which leptin promotes liver fibrogenesis through upregulation of collagen type I expression is not clear. We investigated whether leptin-induced collagen type I is mediated by the Janus kinase-phosphatidylinositol 3-kinase-Akt (JAKs-PI3K-Akt) pathway in a human HSC cell line, LX-2. METHODS: LX-2 cells were treated with or without various inhibitors in the presence of leptin. RESULTS: Leptin increased alpha1(I) collagen mRNA and protein. JAK1, PI3K and Akt were activated after leptin stimulation. AG490, a JAK inhibitor, blocked JAK1 phosphorylation accompanied by inhibition of PI3K and Akt activation as well as alpha1(I) collagen mRNA expression, indicating a JAK1-dependent mechanism. Wortmannin, a PI3K inhibitor, prevented PI3K and Akt activation and resulted in suppression of alpha1(I) collagen mRNA expression, suggesting a PI3K-mediated process. These changes were reproduced by overexpression of the dominant-negative p85alpha mutant. A443654.3, an Akt inhibitor, opposed Akt activation, leading to downregulation of alpha1(I) collagen mRNA. Overexpression of the dominant-negative Akt mutant led to similar alterations. CONCLUSION: Leptin has a direct action on liver fibrogenesis by stimulating alpha1(I) collagen production in activated HSC. The process appears to be mediated by the PI3K/Akt pathway through activated JAK1.
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