Insulin receptor substrate 2 (IRS2)-deficiency delays liver fibrosis associated to cholestatic injury

Abstract

Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 impacts on the hepatic fibrotic process associated to cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2-deficient (IRS2KO) female mice. Histological and biochemical analysis together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSC) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed less histological alterations in the liver, including hepatocyte damage and excess deposition of extracellular matrix components, compared to WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL agreed with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or ERK1/2 inhibition reduced the activation of LX2 cells, a human HSC line, as well as the induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unraveled the signalling pathway mediated by IGF1R-IRS2-ERK1/2-MMP9 as a key axis in regulating HSC activation which might be therapeutically relevant for targeting liver fibrosis.