Dataset Information

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

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.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): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Marcel Schilling

LAB HEAD: Ursula Klingmueller

PROVIDER: PXD043007 | Pride | 2024-01-15

REPOSITORIES: Pride

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Publications

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

Burbano de Lara Sebastian S Kemmer Svenja S Biermayer Ina I Feiler Svenja S Vlasov Artyom A D'Alessandro Lorenza A LA Helm Barbara B Mölders Christina C Dieter Yannik Y Ghallab Ahmed A Hengstler Jan G JG Körner Christiane C Matz-Soja Madlen M Götz Christina C Damm Georg G Hoffmann Katrin K Seehofer Daniel D Berg Thomas T Schilling Marcel M Timmer Jens J Klingmüller Ursula U

Molecular systems biology 20240112 3

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]

PMID: 38216754

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Project description:Background: HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. Treatment with HGF has been shown to accelerate resolution of fibrotic liver lesions in experimental animal models. To formally address the importance of c-Met signaling in hepatocytes in the context of chronic liver injury, we have used hepatocyte-specific Metfl/fl;Alb-Cre+/- conditional knockout mice (KO) and a model of liver fibrosis. Methods: CCl4 was administrated biweekly over a period of 4 weeks (injury phase), and the animals were followed over the next 4 weeks (healing phase). Macroscopic and microscopic changes during the injury and healing phases were monitored by IHC. Deposition of ECM was assessed by Sirius red staining and hydroxiproline content. Activation of hepatic stellate cells (HSC) was estimated by a-SMA using WB and IHC. Expression levels of the selected key fibrotic molecules were evaluated by RT-qPCR and WB. Time-dependent global transcriptomic changes from whole livers and isolated hepatocytes were examined using gene expression microarrays. Results: Loss of HGF/c-Met signaling in hepatocytes altered the hepatic microenvironment and dramatically aggravated hepatic fibrogenesis. Increased liver damage was associated with decreased hepatocyte proliferation, progressive accumulation of HSCs, and delayed fibrinolysis causing increased collagen deposit. Dystrophic calcification of necrotic areas impaired phagocytosis, resulting in sustained inflammatory and fibrogenic signaling further augmenting severity of fibrogenesis. Global gene-expression analysis demonstrated upregulation of key fibrogenic molecules, such as Tgf-Ã¢ and Pdgf-Ã¢, paralleled by a decreased expression of genes important for cell cycle, stress response and regeneration, which could be attributed to the c-Met deficiency in hepatocytes. Additionally, key chemotactic and inflammatory cytokines, including Ccl2, SDF1/Cxcr4 and Spp1, were upregulated in Metfl/fl;Alb-Cre+/- hepatocytes. However, the major pro-fibrotic signaling originated from the non-parenchymal cell compartments, as revealed by cell type-specific gene expression signatures. Conclusion: These results indicate that lack of c-Met signaling in hepatocytes disrupts the balance between extracellular matrix production and degradation and establish a protective role for c-Met against adverse microenvironment leading to the development of fibrotic liver disease. In the present study, we reported a detailed and comprehensive dynamic characterization of the cellular and molecular alterations involved in fibrosis in the liver of c-Met transgenic mice. Liver samples from female animals were collected at various time-points after fibrosis induction using CCL4 ranging from 0 weeks to 3 weeks. Tissue samples were divided into two parts; one was fixed in 10% formalin for histological evaluation and the other was used for RNA analysis.

Dataset Information

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

Publications

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

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