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Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation
Author(s) -
Saxeeeraj K.,
Titus Mark A.,
Ding Xiaokun,
Floyd Jeffrey,
Srinivasan Shanthi,
Sitaraman Shanthi V.,
Anania Frank A.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1847fje
Subject(s) - hepatic stellate cell , protein kinase b , mapk/erk pathway , biology , leptin , microbiology and biotechnology , platelet derived growth factor receptor , cancer research , medicine , endocrinology , chemistry , phosphorylation , growth factor , receptor , biochemistry , obesity
A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cell (HSC) phenotype by both proliferation and inhibition of apoptosis. We provide evidence that leptin is a potent HSC mitogen and dramatically inhibits stellate cell apoptosis. Leptin proved to be as potent an HSC mitogen as platelet‐derived growth factor (PDGF) as assessed by bromodeoxyuridine (BrdU) incorporation in isolated primary HSCs; data using fluorescent propidium iodide (PI) uptake revealed that leptin, like PDGF, increased HSC populations in the S‐ and G 2 /M‐phases of the cell cycle. Leptin resulted in a robust increase in cyclin D1 expression. Using the chemical inhibitor of Janus kinase 2 (Jak2) activity, AG 490, and overexpression of the suppressor of cytokine signaling 3 (SOCS‐3), we show that blockade of leptin receptor (Ob‐Rb) phosphorylation blocks leptin‐induced HSC proliferation. Leptin‐associated phosphorylation of both extracellular regulated kinase (p44/p42, Erk) and Akt is also prohibited. Further, the PI‐3 kinase inhibitor LY294002 and MAPK inhibitor PD98059 were found to significantly reduce leptin‐induced HSC proliferation, thereby indicating that leptin induced HSC proliferation is Akt‐ and Erk‐dependent. Akt was also protective against HSC apoptosis. Leptin abolished both cycloheximide‐induced and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis, demonstrated by reduced caspase‐3 activity, HSC‐TUNEL staining, and DNA fragmentation. We conclude that leptin acts as a direct hepatic stellate cell survival agonist. Importantly, we have demonstrated that leptin‐induced HSC proliferation and survival by Ob‐Rb phosphorylation are both Erk‐ and Akt‐dependent.