• Akt;
  • hepatic fibrosis;
  • leptin;
  • 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.