title: Adiponectin and resistin protect steatotic livers undergoing transplantation.
abstract: OBJECTIVE
  Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion. Controversial roles for adiponectin and related adipocytokines visfatin and resistin have been described in different liver pathologies, nevertheless it is unknown their possible implication in ischemia-reperfusion injury associated with liver transplantation. Our study aimed at characterizing the role of the adiponectin-derived molecular pathway in transplantation with steatotic and non-steatotic liver grafts.
  
  
  METHODS
  Steatotic and non-steatotic liver transplantation was carried out and the hepatic levels of adiponectin, visfatin and resistin were measured and modulated either pharmacologically or surgically.
  
  
  RESULTS
  Steatotic liver grafts exhibited downregulation of both adiponectin and resistin when subjected to transplantation. Adiponectin pre-treatment only protected steatotic grafts and did it so through a visfatin-independent and resistin-dependent mechanism. Adiponectin-derived resistin accumulation activated the PI3K/Akt pathway, unravelling AMPK as an upstream mediator of adiponectin's actions in steatotic grafts. Strategies aimed at increasing adiponectin including either AMPK activators or the induction of ischemic preconditioning (which activates AMPK) increased resistin accumulation, prevented the downregulation of PI3K/Akt pathway and protected steatotic liver grafts. Conversely, PI3K/Akt pathway upregulation and hepatic protection induced by adiponectin were abolished when resistin action was inhibited.
  
  
  CONCLUSIONS
  Our findings reveal a new protective pathway in steatotic liver transplantation, namely AMPK-adiponectin-resistin-PI3K/Akt, which may help develop new strategies aimed at increasing either adiponectin or resistin in the steatotic liver undergoing transplant to ultimately increase organ donor pool and reduce waiting list.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Mónica B
authors.initials: MB
authors.lastname: Jiménez-Castro
authors.forename: Araní
authors.initials: A
authors.lastname: Casillas-Ramírez
authors.forename: Mariana
authors.initials: M
authors.lastname: Mendes-Braz
authors.forename: Marta
authors.initials: M
authors.lastname: Massip-Salcedo
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: María
authors.initials: M
authors.lastname: Elias-Miró
authors.forename: Juan
authors.initials: J
authors.lastname: Rodés
authors.forename: Carmen
authors.initials: C
authors.lastname: Peralta
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D052242:Adiponectin / Q000502:physiology*; D000818:Animals; D016207:Cytokines / Q000502:physiology; D005234:Fatty Liver / Q000601:surgery*; D016031:Liver Transplantation; D054409:Nicotinamide Phosphoribosyltransferase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D052243:Resistin / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D052242:Adiponectin; D016207:Cytokines; D052243:Resistin; C499623:Retn protein, mouse; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: AICAR; ALT; AMP-activated protein kinase; AMPK; ANOVA; AST; Adiponectin; H&E; I/R; Liver transplantation; Ln; Ob; PC; PI3K; Resistin; Steatotic liver grafts; TR; UW; University of Wisconsin; Visfatin; alanine aminotransferase; alpha-glutathione S-transferase; aminoimidazole-4-carboxamide ribonucleoside; analysis of variance; aspartate aminotransferase; hematoxylin and eosin; ischemia-reperfusion; ischemic preconditioning; lean; obese; phosphoinositide-3-kinase; transplantation; α-GST