Leptin stimulates alpha1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway.
OBJECTIVE
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.


CONCLUSIONS
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.
Niu
Liwen
L
School of Pharmacy, Anhui Medical University, Anhui Province, China.
Wang
Xiaohong
X
Li
Jun
J
Huang
Yan
Y
Yang
Zhen
Z
Chen
Feihu
F
Ni
Hongchang
H
Jin
Yong
Y
Lu
Xiongwen
X
Cao
Qi
Q
D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D020738:Leptin; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt