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Insulin-Like Growth Factor Signaling Pathways in Rat Hepatic Stellate Cells: Importance for Deoxyribonucleic Acid Synthesis and Hepatocyte Growth Factor Production¹

Research Center for Endocrinology and Metabolism (S.S., K.W., J.-O.J.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; and Department of Clinical Chemistry and Pathobiochemistry (A.M.G.), Rheinisch-Westfalische Technische Hochschule-University Hospital, D-52057 Aachen, Germany

Address all correspondence and requests for reprints to: Stanko Skrtic, Research Center for Endocrinology and Metabolism, Endocrine Division, Gröna Stråket 8, Sahlgrenska, University Hospital, SE-413 45 Göteborg, Sweden. E-mail: stanko{at}medic.gu.se

It has been shown recently that insulin-like growth factor 1 (IGF-1) increases both DNA synthesis and hepatocyte growth factor (HGF) production in cultured hepatic stellate cells. In this study, we used selective blockers to investigate crucial signaling pathways for these effects of IGF-1 in cultured rat hepatic stellate cells.

Both LY 294002 [a phosphatidylinositol 3-kinase (PI3-K) inhibitor], and rapamycin [a blocker of activation of the serine/threonine p70 S6 kinase (p70^S6K), a molecule downstream from PI3-K] completely reversed the IGF-1-induced stimulation of DNA synthesis. Mitogen-activated protein kinase (MAPK) inhibition by PD 98059 had a less pronounced suppressory effect, although the used PD 98059 dose was fully effective in inhibiting MAPK phosphorylation. Both LY 294002 and PD 98059 lowered the IGF-1-induced increase of HGF in the medium by about 40%, but LY 294002 was 10 times more potent than PD 98059. Inhibition of p70^S6K activation by rapamycin blocked IGF-1-induced DNA synthesis but not the increase in HGF.

In conclusion, PI3-K (and, to some extent, MAPK) signaling pathways seem to be important for IGF-1-stimulated DNA synthesis and HGF production. DNA synthesis also seems to be dependent on rapamycin-sensitive activation of the PI3-K effector p70^S6K.

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