摘要：SummaryThe liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.Graphical abstractDisplay OmittedHighlights•Fgfr3 is important for hepatocyte survival following CCl4-induced liver injury•Fgfr3 in hepatocytes regulates expression of metabolic and pro-fibrotic genes•Fgfr3 protects from extensive fibrosis after chronic CCl4treatment•Fgf receptors have unique, but also overlapping functions in hepatocytesBiological sciences; Cell biology; Molecular biology
