Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease
-
Published:2024-01-12
Issue:
Volume:
Page:
-
ISSN:1744-4292
-
Container-title:Molecular Systems Biology
-
language:en
-
Short-container-title:Mol Syst Biol
Author:
Burbano de Lara SebastianORCID, Kemmer SvenjaORCID, Biermayer Ina, Feiler Svenja, Vlasov Artyom, D’Alessandro Lorenza A, Helm Barbara, Mölders Christina, Dieter YannikORCID, Ghallab AhmedORCID, Hengstler Jan G, Körner ChristianeORCID, Matz-Soja Madlen, Götz ChristinaORCID, Damm Georg, Hoffmann Katrin, Seehofer Daniel, Berg Thomas, Schilling MarcelORCID, Timmer JensORCID, Klingmüller UrsulaORCID
Abstract
AbstractChronic 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 hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
Funder
Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft University of Freiburg Baden-Württemberg
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,Computational Theory and Mathematics,General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Information Systems
Reference59 articles.
1. Abe T, Sakaue-Sawano A, Kiyonari H, Shioi G, Inoue K-i, Horiuchi T, Nakao K, Miyawaki A, Aizawa S, Fujimori T (2013) Visualization of cell cycle in mouse embryos with Fucci2 reporter directed by Rosa26 promoter. Development 140:237–246 2. Adlung L, Kar S, Wagner MC, She B, Chakraborty S, Bao J, Lattermann S, Boerries M, Busch H, Wuchter P et al (2017) Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation. Mol Syst Biol 13:904 3. Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, Cech M, Chilton J, Clements D, Coraor N, Eberhard C et al (2016) The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res 44:W3–W10 4. Allaire M, Gilgenkrantz H (2018) The impact of steatosis on liver regeneration. Horm Mol Biol Clin Investig. https://doi.org/10.1515/hmbci-2018-0050 5. Best DJ, Roberts DE (1975) Algorithm AS 89: the upper tail probabilities of Spearman’s rho. J R Stat Soc Ser C (Appl Stat) 24:377–379
|
|