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Insulin-Like Growth Factors Stimulate Expression of Hepatocyte Growth Factor But Not Transforming Growth Factor ß₁ in Cultured Hepatic Stellate Cells¹

Research Center for Endocrinology and Metabolism (S.S., V.W., S.E., J.-O.J.), Sahlgrenska University Hospital, Göteborg S-413 45, Sweden; and Department of Clinical Chemistry (A.B., A.M.G.), Philipps-University, Marburg D-35033, Germany

Address all correspondence and requests for reprints to: John-Olov Jansson, Research Center for Endocrinology and Metabolism, Endocrine Division, Gröna Stråket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

Hepatic stellate cells (HSC) are located adjacent to hepatocytes and produce hepatocyte growth factor (HGF) in the normal liver, whereas transformed HSC in fibrotic livers produce transforming growth factor ß₁ (TGFß₁), an inhibitor of hepatocyte proliferation. In addition to the endocrine actions of hepatic insulin-like growth factor-I (IGF-I), it also stimulates the proliferation of HSC. In this study we found that addition of IGF-1 (20–500 ng/ml) for 48 h to 2- to 7-day-old primary cultures of rat HSC resulted in a time- and dose-dependent increase by 50–190% of the concentrations of immunoreactive HGF in the medium. The levels of HGF as well as DNA synthesis measured as thymidine incorporation were also enhanced by IGF-II and des(1–3)IGF-I, which has reduced binding to IGF binding proteins. There was no consistent effect of the IGFs on the levels of immunoreactive TGFß₁ or on the total DNA content of the cultures. There was no effect of human GH on medium levels of HGF or TGFß₁, thymidine incorporation, or total DNA content. IGF-I increased the abundance of HGF messenger RNA, as measured by the RNase protection/solution hybridization technique, whereas there was no effect on TGFß₁ or glyceraldehyde phosphate dehydrogenase messenger RNA. The results suggest that IGFs stimulate the production of HGF but not TGFß₁ by HSC in vitro.

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