Cross-talk between sirtuin 1 and high-mobility box 1 in steatotic liver graft preservation

Abstract

[Background] Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide +–dependent histone deacetylase that regulates various pathways involved in ischemia-reperfusion injury (IRI). Moreover, high-mobility group box 1 protein (HMGB1) has also been involved in inflammatory processes during IRI. However, the roles of both SIRT1 and HMGB1 in liver preservation is poorly understood. In this communication, we evaluated the potential relationship between SIRT1 and HMGB1 in steatotic and non-steatotic liver grafts preserved in Institute Georges Lopez solution (IGL-1) preservation solution enriched or not enriched with trimetazidine (TMZ).

[Methods] Steatotic and non-steatotic livers were preserved in IGL-1 preservation solution (24 hours, 4°C), enriched or not enriched with TMZ (10 μmol/L), and then submitted to ex vivo reperfusion (2 hours; 37°C). Liver injury (AST/ALT) and function (bile output, vascular resistance) were evaluated. SIRT1, HMGB1, autophagy parameters (beclin-1, LC3B), PPAR-γ, and heat-shock protein (HO-1, HSP70) expression were determined by means of Western blot. Also, we assessed oxidative stress, mitochondrial damage (glutamate dehydrogenase), and TNF-α levels.

[Results] Elevated SIRT1 and enhanced autophagy were found after reperfusion in steatotic livers preserved in IGL-1+TMZ when compared with IGL-1. However, these changes were not seen in the case of non-steatotic livers. Also, HO-1 increases in the IGL-1 + TMZ group were evident only in the case of steatotic livers, whereas HSP70 and PPAR-γ protein expression were enhanced only in non-steatotic livers. All reported changes were consistent with decreased liver injury diminution, ameliorated hepatic function, and decreased TNF-α and HMGB levels. In addition, the oxidative stress and mitochondrial damage were efficiently prevented by the IGL-1 + TMZ use.

[Conclusions] SIRT1 is associated with HMGB1 decreases and increased autophagy in steatotic livers, contributing to increased tolerance to cold IRI.