Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways

Insulin and insulin-like growth factor (IGF-1) are mitogenic for fibroblast s and smooth muscle cells. IGF-1 increases in inflamed and fibrotic tissues and induces proliferation of rat hepatic stellate cells (HSC). This study evaluates the potential roles of these hormones in the development of liver fibrosis. Insulin and IGF-1 receptor expression was evaluated by immunohis tochemistry in both cultured human HSC and human liver tissue. Phosphorylat ion of both 70-kd S6 kinase and extracellular-regulated kinase (ERK), cell proliferation, type I collagen gene expression, and accumulation in HSC cul ture media were evaluated by Western blot, immunohistochemistry for bromode oxyuridine (BrdU), Northern Mot, and enzyme-linked immunosorbent assay, res pectively. Insulin and IGF-1 receptors were detected in HSC in vitro and in liver sections from patients with chronic active hepatitis. Insulin and IG F-1 induced 70-kd S6 kinase phosphorylation in HSC, whereas IGF-1 only indu ced ERK phosphorylation. Insulin and IGF-I stimulated HSC proliferation in a dose-dependent fashion, with IGF-1 being four to five times more potent t han insulin. Cell exposure to specific inhibitors showed that both phosphat idylinositol 3-kinase (PU-K) and ERK are involved in IGF-l-induced mitogene sis, whereas insulin stimulated mitogenesis through a PD-K-dependent ERK-in dependent pathway. IGF-1 increased type I collagen gene expression and accu mulation in HSC culture media through a PI3-K- and ERK-dependent mechanism. In conclusion, insulin and IGF-1, which stimulate HSC mitogenesis and coll agen synthesis, may act in concert to promote liver fibrosis in vivo by a d ifferential activation of PI3-K- and ERK1-dependent pathways.