Improvement of steatotic rat liver function with a defatting cocktail during ex situ normothermic machine perfusion is not directly related to liver fat content

Abstract

There is a significant organ shortage in the field of liver transplantation, partly due to a high discard rate of steatotic livers from donors. These organs are known to function poorly if transplanted but make up a significant portion of the available pool of donated livers. This study demonstrates the ability to improve the function of steatotic rat livers using a combination of ex situ machine perfusion and a "defatting" drug cocktail. After 6 hours of perfusion, defatted livers demonstrated lower perfusate lactate levels and improved bile quality as demonstrated by higher bile bicarbonate and lower bile lactate. Furthermore, defatting was associated with decreased gene expression of pro-inflammatory cytokines and increased expression of enzymes involved in mitochondrial fatty acid oxidation. Rehabilitation of marginal or discarded steatotic livers using machine perfusion and tailored drug therapy can significantly increase the supply of donor livers for transplantation.

Ex vivo machine perfusion: current applications and future directions in liver transplantation

“…Thus, although the near physiologic state maintained by NEVLP is beneficial in and of itself, it may additionally serve as a platform to allow further optimization of marginal liver grafts by drug application during ex vivo machine perfusion. Currently, several groups are working on protocols for "defatting" of steatotic liver grafts, with the idea of decreasing the detrimental effect of IRI on these organs after reperfusion [69][70][71]. Indeed, a recently published report of the Zürich group, preserving injured human livers for 7 days by ex vivo machine perfusion, encourages research towards drug application as the available period for ex vivo drug treatment is significantly prolonged [72].…”

Defatting strategies in the current era of liver steatosis

“…subjected steatotic rat livers to NEsLP with a defatting drug cocktail. 43 The defatting cocktail was based on drugs that were proven to be effective in cell culture models: forskolin, scoparone, hypericin, visfatin, L-carnitine, and amino acids. After 6 h of perfusion, the defatted livers showed increased viability, demonstrated by lower perfusate lactate and better bile quality (lower bile lactate and higher bile bicarbonate).…”

“…Perfusion with GDNF also resulted in a significantly higher reduction in TG content. Moreover, perfusion with GDNF proved more effective in decreasing TG content than perfusion with the defatting cocktail.In a recent study, Raigani et al subjected steatotic rat livers to NEsLP with a defatting drug cocktail(44). The defatting cocktail was based on drugs that were proven to be effective in cell culture models: forskolin, scoparone, hypericin, visfatin, Lcarnitine, and amino acids.…”

Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury

“…Interestingly, another study investigating the use of a cocktail of defatting agents during NMP in Zucker rats showed intracellular lipid content of perfused liver was decreased by 50% and increased lipid oxidation [ 238 ]. Likewise, when L-carnitine was added to a cocktail of defatting agents a reduction of macrosteatosis from 42.5% to 8.5% after NMP was observed [ 241 ].…”