Adiponectin and resistin protect steatotic livers undergoing transplantation

Abstract

Background & aims: 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.

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.