Basal MET Phosphorylation as an Indicator of Hepatocyte Dysregulation in Liver Disease

Model of the Month created by Dr Svenja Kemmer, Jens Timmer’s Group, University of Freiburg, Germany, in close collaboration with Ursula Klingmüller’s Lab, DKFZ Heidelberg, Germany 
Original model – MODEL2306280002

Introduction

Chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), are a growing global health concern. Although the structural hallmark of MASLD—lipid droplet accumulation in hepatocytes—is well known [1], the molecular mechanisms linking these changes to disease progression remain unclear.

In our recent study, conducted in the frame of the LiSyM-Cancer Network funded by the German Federal Ministry for Education and Research, we sought to unravel how high-fat, high-sugar diets influence intracellular signalling in hepatocytes. Using a dynamic mathematical model of hepatocyte growth factor (HGF) signal transduction, we identified the basal phosphorylation of the MET receptor as a key indicator of hepatocyte dysregulation. Not only does this elevated basal MET activity disturb signalling dynamics in steatotic hepatocytes, but it also correlates with patient outcomes following liver surgery [2].

Model

The mathematical model developed for our approach describes HGF-induced signalling via the MET receptor tyrosine kinase, which activates the MAPK and PI3K/AKT pathways—critical for liver regeneration [3]. Based on coupled ordinary differential equations (ODEs), the model integrates these pathways along with the mTOR nutrient-sensing system (Figure 1).

We calibrated the model using quantitative, time- and dose-resolved immunoblotting data from primary mouse hepatocytes isolated from mice fed with a standard (SD) or a Western diet (WD), as well as global proteomics data. The resulting model included 23 molecular species and 26 reactions, describing both dynamic processes and basal protein abundances.

Figure 1: Scheme of the mathematical model capturing HGF-induced signal transduction via the MAPK cascade (blue), the PI3K pathway (red) and mTOR signalling (green). All parameter values were implemented as identical for WD and SD hepatocytes except for protein abundances and the basal MET phosphorylation rate, indicated by the red box.

Results

Our experimental data showed that WD hepatocytes exhibit elevated basal MET phosphorylation, reduced AKT activation, and an increased HGF-independent proliferative behaviour. Analysing the system with our calibrated mathematical model, we could show that only one dynamic parameter, namely the basal phosphorylation rate of MET, could simultaneously explain the observed signalling differences between SD and WD hepatocytes. All other parameters, including degradation and activation rates, could remain the same if we accounted for this single change alongside 11 altered protein abundances. The resulting model trajectories along with measured phosphorylation dynamics are shown in Figure 2. These findings suggested that the basal phosphorylation of MET acts as an integrator of metabolic alterations, triggering a shift in how hepatocytes interpret proliferative signals.

To test the clinical relevance of our findings, we adapted the mathematical model to primary human hepatocytes from patients undergoing liver surgery. The basal MET phosphorylation rate, estimated by model calibration, correlated significantly with post-operative complication scores and hospitalization times, offering a promising predictive marker for liver health and recovery potential.

Figure 2: Model trajectories with time-resolved immunoblot measurements. Data points are displayed as dots along with error bars representing 1σ confidence interval estimated from biological replicates (n = 3–9 per diet and time point) using a combined scaling and error model. Model trajectories are depicted as solid lines.

Discussion

Our mathematical model highlights how systems biology can pinpoint a single mechanistic alteration—in this case, an increased basal MET phosphorylation rate—that rewires proliferative signal transduction in hepatocytes exposed to the Western diet.

By combining dynamic modelling, proteomics, and clinical data, we show that elevated basal MET phosphorylation reduces AKT activation through a feedback mechanism involving the mTORC1–S6K–IRS1 axis and leads to proliferation even in the absence of growth factors, a phenomenon observed in both mouse and human hepatocytes.

Clinically, this model-based metric could provide pre-operative insight into patient liver status, improving risk stratification in liver surgery. While current scores like Clavien-Dindo are based on postoperative data [4], basal pMET might serve as a preoperative molecular marker of regenerative capacity.

References

[1] Huang DQ et al. (2021) Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterology & Hepatology 18:223–238

[2] Burbano de Lara S, Kemmer S and Biermayer I et al. (2024) Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease. Mol Systems Biology 20:187 – 216

[3] Kiseleva YV et al. (2021) Molecular pathways of liver regeneration: A comprehensive review. World J Hepatol 13: 270-290

[4] Dindo D et al. (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213