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

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 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2-deficient (IRS2KO) female mice. Histological and biochemical analyses, 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 (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with 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 corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced 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 unravelled 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.This work was supported by the Instituto de Salud Carlos III (ISCIII/FEDER) (PI17/00535 and CIBEREHD) to C.G.-M.; Ministerio de Ciencia e Innovación (MICINN/FEDER) (RTI2018-094052-B-100), Comunidad de Madrid (S2017/BMD-3684 MOIR2-CM), Instituto de Salud Carlos III (ISCIII/FEDER) (CIBERDEM) and H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant agreement number 721236) to A.M.V.; Instituto de Salud Carlos III (ISCIII/FEDER) (CP14/00181 and PI16/00823) and Beca Eduardo Gallego 2016 (Fundación Francisco Cobos) to A.G.-R.Peer reviewe