title: Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation.
abstract: OBJECTIVE
  Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD).
  
  
  METHODS
  rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects.
  
  
  RESULTS
  CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD(+)/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK.
  
  
  CONCLUSIONS
  rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Castaño
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Larequi
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Belza
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), University of Valladolid, 47003 Valladolid, Spain; CIBERDEM Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036 Barcelona, Spain.
authors.forename: Alma M
authors.initials: AM
authors.lastname: Astudillo
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez-Ansó
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), University of Valladolid, 47003 Valladolid, Spain; CIBERDEM Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036 Barcelona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Josepmaria
authors.initials: J
authors.lastname: Argemi
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Aragon
authors.affiliation: Department of Nutrition, Food Sciences, Physiology and Toxicology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Moreno-Aliaga
authors.affiliation: Institute of Biomedicine (IBiS), University of Sevilla, 41013 Sevilla, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntane
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; CIBEREHD Clinic of the University of Navarra, 31008 Pamplona, Spain. Electronic address: jprieto@unav.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain. Electronic address: mbustos@unav.es.
authors.forename: Matilde
authors.initials: M
authors.lastname: Bustos
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D056564:Sirtuin 1 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011994:Recombinant Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C092073:cardiotrophin 1; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: AMPK; Cardiotrophin-1; Fatty acid oxidation; Lipogenesis; Non-alcoholic fatty liver disease (NAFLD)