Characterization and regulation of insulin-like growth factor binding proteins (igfbps) in human liver fat storing cells (fsc)

IGF-I may play a role in the proliferative and fibrotic response of FSC during liver inflammation. IGF-l-mediated effects are modulated by IGFBPs. FSC secrete IGF-I and IGF binding activity; however, the specific IGFBPs produced by these cells and the factors involved in their regulation are unknown. We examined FSC for IGFBP protein and IGFBP-1 to -6 mRNA expression. Western ligand blot analysis and RNase protection assays demonstrated that FSC express IGFBP-2 to -6 mRNAs and secrete the corresponding proteins. Since IGF-I, PDGF and TGF-beta stimulate FSC proliferation and/or matrix production, we tested their effect on IGFBPs released by FSC. IGF-I induced IGFBP-3 and -, and decreased IGFBP4 protein levels. TGF-beta induced IGFBPS and decreased IGFBP5 proteins. PDGF failed to regulate IGFBPs compared to control. TGF-beta, but not IGF-I, increased IGFBPS mRNA levels at 24 hrs, an effect that persisted for 72 hrs. Recombinant IGFBP3 was tested for its effect on IGF-l-induced mitogenesis. IGFBPS inhibited IGF-l-stimulated DNA synthesis in a dosedependent manner with a peak effect observed at 60 nM IGFBPS. Expression of IGFBP-2 to -6 by FSC suggests that these proteins locally modulate autocrine and paracrine effects of IGF-I in the liver. Cytokines such as IGF-I and TGF-beta may indirectly influence the effect of IGF-I on FSC growth and matrix production via the release of IGFBPS.