The central role of the c-Met pathway in rebuilding the liver

Thorgeirsson, Snorri S.

doi:10.1136/gutjnl-2012-302234

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…c-Met is implicated in a variety of metabolic processes and serves an essential stimulus for effective repair of liver damage in response to different damaging agents (Thorgeirsson 2012). To assess the role of c-Met under a stress condition, we exposed MetKO and WT mice to a 30-day course of hypercholesterolemic diet (HC) and compared the extent of liver injury in WT and MetKO mice maintained on normal chow and HC diet.…”

Section: Resultsmentioning

confidence: 99%

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

et al. 2016

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Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30 days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.

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Section: Resultsmentioning

confidence: 99%

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

et al. 2016

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“…The role of HGF/c-met axis in liver pathophysiology has been extensively investigated with a particular light on aspects regarding liver regeneration, hepatocyte proliferation, and apoptosis [19]. Moreover, activation of this signaling pathway has been repeatedly reported to exert hepatoprotective effects against experimental conditions characterized by oxidative stress [20, 21].…”

Section: Discussionmentioning

confidence: 99%

Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte‐Specific c‐met Deletion during the Progression of NASH

Ramadori

Drescher

Erschfeld

et al. 2017

Oxidative Medicine and Cellular Longevity

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We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx), single c-met knockouts (c-metΔhepa), and double c-met/Keap1 knockouts (met/Keap1Δhepa) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Δhepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c-metΔhepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver-infiltrating cells and the exacerbation of fibrosis progression observed in c-metΔhepa livers was significantly inhibited in met/Keap1Δhepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis.

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“…( 19 ) Within this process, the activation of HGF/MET signaling pathway has been demonstrated to be 1 of the essential mechanisms that lead hepatocytes into the cell cycle after hepatectomy. ( 20 ) Following resection, HGF protein levels in plasma typically rise, ( 21 ) but liver fibrosis is known to prevent this process. The lack of HGF induction on a cirrhotic background was fully confirmed in our study (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Mesenchymal‐Epithelial Transition Factor‐Agonistic Antibody Accelerates Cirrhotic Liver Regeneration and Improves Mouse Survival Following Partial Hepatectomy

Que

et al. 2021

Liver Transpl

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Small‐for‐size syndrome (SFSS) is a common complication following partial liver transplantation and extended hepatectomy. SFSS is characterized by postoperative liver dysfunction caused by insufficient regenerative capacity and portal hyperperfusion and is more frequent in patients with preexisting liver disease. We explored the effect of the Mesenchymal‐epithelial transition factor (MET)‐agonistic antibody 71D6 on liver regeneration and functional recovery in a mouse model of SFSS. Male C57/BL6 mice were exposed to repeated carbon tetrachloride injections for 10 weeks and then randomized into 2 arms receiving 3 mg/kg 71D6 or a control immunoglobulin G (IgG). At 2 days after the randomization, the mice were subjected to 70% hepatectomy. Mouse survival was recorded up to 28 days after hepatectomy. Satellite animals were euthanized at different time points to analyze liver regeneration, fibrosis, and inflammation. Serum 71D6 administration significantly decreased mouse mortality consequent to insufficient regeneration of the cirrhotic liver. Analysis of liver specimens in satellite animals revealed that 71D6 promoted powerful activation of the extracellular signal‐regulated kinase pathway and accelerated liver regeneration, characterized by increased liver‐to‐body weight, augmented mitotic index, and higher serum albumin levels. Moreover, 71D6 accelerated the resolution of hepatic fibrosis as measured by picrosirius red, desmin, and α–smooth muscle actin staining, and suppressed liver infiltration by macrophages as measured by CD68 and F4/80 staining. Analysis of gene expression by reverse‐transcription polymerase chain reaction confirmed that 71D6 administration suppressed the expression of key profibrotic genes, including platelet‐derived growth factor, tissue inhibitor of metalloproteinase 3, and transforming growth factor‐β1, and of key proinflammatory genes, including tumor necrosis factor‐α, interleukin‐1β, chemokine (C‐C motif) ligand 3, and chemokine (C‐C motif) ligand 5. These results suggest that activating the MET pathway via an hepatocyte growth factor–mimetic antibody may be beneficial in patients with SFSS and possibly other types of acute and chronic liver disorders.

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The central role of the c-Met pathway in rebuilding the liver

Cited by 7 publications

References 11 publications

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte‐Specific c‐met Deletion during the Progression of NASH

A Mesenchymal‐Epithelial Transition Factor‐Agonistic Antibody Accelerates Cirrhotic Liver Regeneration and Improves Mouse Survival Following Partial Hepatectomy

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