JAK/STAT pathway mediates leptin-induced Ⅰ collagen mRNA expression in human hepatic stellate cells / 中国药理学通报

ABSTRACT

Aim To investigate the effects of leptin on ?1(Ⅰ) collagen mRNA expression and protein production, and the roles of Janus kinase/signal transducers and activators transcription(JAK/STAT) signaling transduction pathway in increased ?1(Ⅰ) collagen mRNA expression stimulated by leptin in activated hepatic stellate cells(HSCs).Methods Firstly, ?1(Ⅰ) collagen mRNA expression and protein production as well as JAK1 and STAT3 phosphorylation induced by leptin at different doses in a human HSC cell line, LX-2 were determined by RT-PCR, ELISA, and Western-blot.Secondly, the effects of JAK1 inhibitor AG490 on JAK1 phosphorylation and ?1(Ⅰ) collagen mRNA expression stimulated by leptin were detected by Western blot and RT-PCR. Thirdly, the roles of AG490 and transfection with STAT3 antisense oligonucleotide(STAT3-ASON) in STAT3 phosphorylation after leptin were detected by Western blot. Finally, the effect of transfection with STAT3-ASON on ?1(Ⅰ) collagen mRNA expression after leptin was measured by RT-PCR.Results Leptin increased ?1(Ⅰ) collagen mRNA expression and protein production in a dose-dependent manner in LX-2, reaching a maximal level at 80 ?g?L-1 leptin. In addition, phosphorylation of JAK1 and STAT3 after leptin exhibited a time-dependent effect. Besides, JAK1 inhibitor AG490 completely blocked JAK1 and STAT3 phosphorylation and increased in ?1(Ⅰ) collagen gene expression after leptin in LX-2. Transfection with STAT3-ASON blocked STAT3 phosphorylation and increased ?1(Ⅰ) collagen mRNA by leptin in LX-2.Conclusion Leptin had a direct action on liver fibrogenesis by stimulating ?1(Ⅰ) collagen mRNA expression and protein production in activated HSC, and JAK/STAT signaling transduction pathway was involved in the process. JAK1 inhibitor AG490 and transfection with STAT3-ASON blocked the transduction pathway effectively in LX-2. Leptin may be an important factor in the development of hepatic fibrosis. Activated JAK1 and STAT3 signaling in human HSC line provided a novel molecular target for therapeutic intervention of liver fibrosis.