Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis

Background and Aims: Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis. Methods: Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals. Results: Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis. Conclusion: The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.