Protective role of the secreted tyrosine kinase VLK in liver homeostasis and regeneration

Abstract

Background & Aims: Vertebrate lonesome kinase (VLK) is the only known extracellular tyrosine kinase, but its physiological functions are largely unknown. Here we aimed to investigate the role of VLK-dependent extracellular protein phosphorylation in liver homeostasis and regeneration. Methods: A hepatocyte-specific Vlk knockout mouse was generated and characterized using histology, immunofluorescence and histochemical staining, as well as bile acid and gene expression analysis. In addition, the mice were chronically treated with carbon tetrachloride (CCl4) to induce liver fibrosis. Finally, an in vitro system was established to study paracrine functions of VLK. Results: We established VLK-deficient hepatocyte progenitor cells from primary hepatocytes of Vlk knockout mice. These cells produce a secretome in vitro, which promotes their own proliferation in 3D spheroids as well as proliferation of cultured fibroblasts. In vivo, mice with hepatocyte-specific knockout of VLK develop steatosis with signs of inflammation and perivascular fibrosis upon aging, combined with expansion of liver progenitor cells. In response to chronic CCl4 liver injury, the pattern of deposited collagen is significantly altered in the VLK-deficient mice. Conclusions: These results support a key function for VLK in maintaining liver homeostasis and control of collagen deposition through modulation of the hepatocyte secretome and identify extracellular protein phosphorylation as a key regulator of liver homeostasis, repair and disease.