Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Abstract

(Figure presented.) Primary hepatocytes from a preclinical mouse model fed with high-sugar and high-fat diet are used to develop a data-based mathematical model that identifies the basal phosphorylation rate of the tyrosine kinase receptor MET as the main dysregulated parameter driving fatty liver disease. An increase in phosphorylated MET and a strong downregulation of the PI3K-AKT pathway in response to hepatocyte growth factor (HGF) stimulation are hallmarks of primary hepatocytes derived from mice exposed to a high-fat and high-sugar “Western” diet. Dynamic pathway modeling of HGF signal transduction combined with proteomics identifies elevated basal MET phosphorylation rate as the main driver of altered signaling and increased proliferation. Model-adaptation to primary human hepatocytes reveals that patient-specific variability in basal MET phosphorylation correlates with patient outcome after liver surgery.