Insulin increases type I collagen synthesis in hepatic stellate cells via α5β1 integrin.

Aim: A direct effect of insulin on the synthesis of extracellular matrix proteins has been described in extrahepatic organs. The current study investigates the role of insulin in type I collagen production in hepatic stellate cells (HSCs). Methods: Primary HSC cultures from wild-type mice and from L-SACC1 transgenic mice that exhibit hyperinsulinemia and resultant insulin resistance due to a defect in hepatic insulin clearance were used. Results: Insulin significantly increased type I collagen synthesis in HSC primary cultures in the presence of high but not low glucose concentrations. Although HSCs contain a functional, insulin-activated PI3 kinase signaling pathway, insulin increases type I collagen synthesis by mechanisms independent of PI3 kinase. Insulin stimulated α5β1 integrin levels and phosphorylation of focal adhesion kinase, a major signaling mediator in the integrin pathway. In addition, α5β1 integrin siRNA interference abolished insulin-mediated type I collagen synthesis by HSCs. L-SACC1 mice showed increased hepatic collagen deposition as compared to wild-type mice. HSCs isolated from L-SACC1 mice synthesize more type I collagen and α5β1 integrin than HSCs isolated from wild-type controls. Conclusion: Insulin exerts a direct profibrotic impact on HSCs by an α5β1 integrin-mediated mechanism, independently of the PI3 kinase signaling pathway. Thus, chronic hyperinsulinemia may potentiate liver collagen deposition in insulin resistance states. This likely increases the risk of significant fibrosis burden in chronic liver disease associated with insulin resistance.