title: Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress.
abstract: 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 30days 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.
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA; Departamento de Ciencias de la Salud, Universidad Autonoma Metropolitana Iztapalapa, Mexico, DF, Mexico.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gomez-Quiroz
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Daekwan
authors.initials: D
authors.lastname: Seo
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA; Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Seung-Bum
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Departamento de Ciencias de la Salud, Universidad Autonoma Metropolitana Iztapalapa, Mexico, DF, Mexico.
authors.forename: Ma Concepcion
authors.initials: MC
authors.lastname: Gutierrez-Ruiz
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Conner
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Factor
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: 1st Department of Medicine, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: marquarj@uni-mainz.de.
authors.forename: Jens U
authors.initials: JU
authors.lastname: Marquardt
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation; D008055:Lipids / Q000633:toxicity*; D008111:Liver Function Tests; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002791:Cholesterol, Dietary; D008055:Lipids; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D005978:Glutathione
keywords: Cholestasis; Cholesterol; Oxidative stress; c-Met