Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors

The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended-criteria donors, such as steatotic donors after brain death (DBDs) or cardiocirculatory death (DCDs). Nevertheless, steatosis, brain death, and cardiocirculatory death are key risk factors for poor LT outcomes. Herein, the role and therapeutic usefulness of several adipocytokines was investigated to protect such grafts from extended-criteria donors. Sprague rats with nutritionally induced steatosis were used in an experimental LT model with grafts from DBDs or DCDs. Adiponectin, resistin, and visfatin were measured and pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of either DBD or DCD LT. Brain death increased adiponectin and reduced resistin. Adiponectin harmed steatotic and nonsteatotic DBD grafts, via a resistin-dependent mechanism; restraining adiponectin increased resistin, reducing damage. Resistin treatment protected both types of DBD grafts, whereas suppressing it increased damage. This adiponectin-resistin pathway was dependent on protein kinase C. In DCD LT, adiponectin and resistin were not modified in nonsteatotic grafts, but reduced in steatotic ones. Adiponectin or resistin treatments protected steatotic grafts: hepatic adiponectin activated AMP-activated protein kinase ; hepatic resistin increased phosphatidylinositol 3-kinase-Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. These data suggest that pharmacologic modulation of adiponectin and resistin as therapies might potentially be translated to clinical studies to improve surgical outcomes for LT from extended-criteria donors.