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Leptin stimulates α1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway.
- Source :
- Liver International; Nov2007, Vol. 27 Issue 9, p1265-1272, 8p, 5 Black and White Photographs, 1 Graph
- Publication Year :
- 2007
-
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 α1(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 α1(I) collagen mRNA expression, indicating a JAK1-dependent mechanism. Wortmannin, a PI3K inhibitor, prevented PI3K and Akt activation and resulted in suppression of α1(I) collagen mRNA expression, suggesting a PI3K-mediated process. These changes were reproduced by overexpression of the dominant-negative p85α mutant. A443654.3, an Akt inhibitor, opposed Akt activation, leading to downregulation of α1(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 α1(I) collagen production in activated HSC. The process appears to be mediated by the PI3K/Akt pathway through activated JAK1. [ABSTRACT FROM AUTHOR]
- Subjects :
- LEPTIN
COLLAGEN
MESSENGER RNA
CELL lines
LIVER
Subjects
Details
- Language :
- English
- ISSN :
- 14783223
- Volume :
- 27
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Liver International
- Publication Type :
- Academic Journal
- Accession number :
- 26913559
- Full Text :
- https://doi.org/10.1111/j.1478-3231.2007.01582.x