REGULATION OF ADIPONECTIN AND RESISTIN IN LIVER TRANSPLANTATION PROTECTS GRAFTS FROM EXTENDED-CRITERIA DONORS.

Abstract

The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended criteria donors (ECDs), 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. We investigated the role and therapeutical usefulness of several adipocytokines to protect such grafts from ECD. Sprague rats with nutritionally-induced steatosis were used in an experimental LT model with grafts from DBD or DCD. Adiponectin, resistin, and visfatin were measured, pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of neither DBD nor 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 PKC. 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 AMPK; hepatic resistin increased PI3k-Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. Therefore, pharmacological modulation of adiponectin and resistin resulted in therapies that potentially might be translated to clinical studies to improve surgical outcomes for LT from ECD.