The orphan receptor GPR176 in hepatic stellate cells exerts a profibrotic role during chronic liver diseases

Background & Aims Chronic liver disease (CLD) remains a global health issue associated with a significant burden of disease. Liver fibrosis, one of the hallmarks of CLD, is characterized by the activation of hepatic stellate cells (HSCs) that gain pro-fibrotic characteristics including increased extracellular matrix protein production. Currently, no anti-fibrotic therapies are available in the clinic partly due to the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for anti-fibrotic drug development. Methods Small interfering RNA-mediated knock-down of GPR176 was used to assess its in vitro function in HSCs and precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed in the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knock-out mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets. Results We identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knock-down of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of Gpr176 does not affect liver homeostasis, but Gpr176-/- mice develop less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression is correlated with in vitro HSC activation and with fibrosis stage in patients suffering from CLD. Conclusions GPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific anti-fibrotic candidate to treat CLD. Impact and implications The lack of effective anti-fibrotic drugs is partly due to insufficient knowledge about the mechanisms involved in liver fibrosis development. We demonstrate G-protein coupled receptor 176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens avenues for the development of targeted interventions.