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Hepatology. 2002 Apr;35(4):762-71.

Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice.

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Hepatology Section, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA.


Leptin is a 16-kd hormone that mediates a range of metabolic effects by using a transduction pathway from the long form of the leptin receptor, OB-R(L,) through Janus kinase-signal transducer and activator of transcription (Jak-Stat) signaling components. Leptin is produced by hepatic stellate cells (HSCs) but only following their "activation." Because activation of stellate cells is a central event in the fibrotic response to liver injury, we hypothesized that leptin may directly stimulate fibrogenesis in activated stellate cells via OB-R(L). We analyzed leptin receptors and their signaling partners in a stellate cell line (HSC-T6) as well as in primary stellate cell isolates. We also examined the effect of leptin on stellate cell expression of alpha(2)(I) collagen messenger RNA (mRNA) levels by ribonuclease protection analysis (RPA). Finally, we examined the role of leptin in in vivo fibrogenesis by inducing a wounding response in ob/ob mice, which lack functional leptin. HSC-T6 and culture-activated stellate cells expressed OB-R(L). Scatchard analysis verified specific binding of leptin to HSCs, with an association constant (K(d)) equal to 660 +/- 5.8 pmol/L. Exposure of HSCs to leptin resulted in significant increases in alpha(2)(I) collagen mRNA expression. Transient transfection with a promoter reporter construct showed a 3-fold increase in alpha(2)(I) collagen transgene activity. Leptin stimulated activation of Stat3 in activated HSCs. Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant alpha-smooth muscle actin staining. In conclusion, these results indicate that leptin is profibrogenic in activated HSCs and can signal via the Jak-Stat pathway. Up-regulation of leptin signaling in liver injury could contribute to enhanced fibrogenesis, particularly in states in which leptin levels are high.

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