Proteomics

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Increased Basal MET phosphorylation is a Hallmark of Hepatocyte Dysregulation in Liver Disease: Mouse


ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Non-alcoholic Fatty Liver Disease

SUBMITTER: Marcel Schilling  

LAB HEAD: Ursula Klingmüller

PROVIDER: PXD041563 | Pride | 2024-01-15

REPOSITORIES: Pride

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Publications


Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary he  ...[more]

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