Leptin stimulates α1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway
Article first published online: 3 OCT 2007
Volume 27, Issue 9, pages 1265–1272, November 2007
How to Cite
Niu, L., Wang, X., Li, J., Huang, Y., Yang, Z., Chen, F., Ni, H., Jin, Y., Lu, X. and Cao, Q. (2007), Leptin stimulates α1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway. Liver International, 27: 1265–1272. doi: 10.1111/j.1478-3231.2007.01582.x
- Issue published online: 3 OCT 2007
- Article first published online: 3 OCT 2007
- Received 5 October 2006accepted 5 August 2007
- hepatic fibrosis;
- phosphatidylinositol 3-kinase (PI3K)
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.