Liver defatting: an alternative approach to enable steatotic liver transplantation

Abstract

Macrovesicular steatosis in greater than 30% of hepatocytes is a significant risk factor for primary graft nonfunction due to increased sensitivity to ischemia reperfusion (I/R) injury. The growing prevalence of hepatic steatosis due to the obesity epidemic, in conjunction with an aging population, may negatively impact the availability of suitable deceased liver donors. Some have suggested that metabolic interventions could decrease the fat content of liver grafts prior to transplantation. This concept has been successfully tested through nutritional supplementation in a few living donors. Utilization of deceased donor livers, however, requires defatting of explanted organs. Animal studies suggest that this can be accomplished by ex vivo warm perfusion in a time scale of a few hours. We estimate that this approach could significantly boost the size of the donor pool by increasing the utilization of steatotic livers. Here we review current knowledge on the mechanisms whereby excessive lipid storage and macrosteatosis exacerbate hepatic I/R injury, and possible approaches to address this problem, including ex vivo perfusion methods as well as metabolically induced defatting. We also discuss the challenges ahead that need to be addressed for clinical implementation.

Figure 1. Histological appearance of defatted steatotic livers procured from 14- to 15-week-old Zucker rats

Livers were examined before and after 3 h of normothermic perfusion in a recirculating perfusion system. (A, B) Normal lean and fatty livers before perfusion. (C) Fatty liver after perfusion with control vehicle solution. (D) Fatty liver after perfusion with a solution containing a cocktail of defatting agents. Right hand panels are higher magnifications of the left hand panels. Reproduced with permission from reference (28).

Figure 2. TG metabolism in steatotic hepatocytes

Lipids are primarily stored in the form of TG inside lipid droplets which are coated with perilipins. Perilipins control access of the stored TG to cytosolic lipases, which liberate free fatty acids (FFA). FFAs can then undergo oxidation through mitochondrial ²-oxidation. FFA and MG translocate to the ER, where they can be reesterified to TG and packaged into VLDL, which is then secreted out of the cells. Major lipid metabolic pathways, including those involved in the removal of TG from steatotic hepatocytes are illustrated. Addition of potential defatting agents that target some of these pathways, such as forskolin, L-carnitine, amino acids and choline, to the perfusate are shown here and discussed further in the text. The dashed arrow represents indirect activation of protein kinase A by forskolin. TG, triglyceride; FFA, Free fatty acid; DG, diacylglycerol; MG, monoacylglycerol; VLDL, very low density lipoprotein; CPT-1, carnitine palmitoyltransferase-1; ER, endoplasmic reticulum; ATP, adenosine triphosphate.