The Role of Sphingosine‐1‐Phosphate Activity in Liver Preservation Injury

Abstract

Lipid signaling molecules, such as lysophosphatidic acid (LPA) and sphingosine‐1‐phosphate (S1P), act as growth and survival factors, and may be involved in liver preservation injury. Recent studies have proposed that there is a cytoskeletal component of preservation injury involving cytoskeletal linker proteins called ERM proteins. In preservation injury, moesin (the predominant ERM protein in the liver) is dysregulated, and found in its inactive, closed conformation. We hypothesize that serum‐derived growth factors (like LPA and/or S1P) may control known upstream regulators of moesin, RhoA and Rho kinase (ROK), which ultimately control moesin functionality and cell adhesion to the basement membrane. To begin testing this hypothesis, we demonstrated that inhibition of RhoA and ROK potentiated preservation injury in hepatocyte models of hypothermic ischemia. Preliminary data suggests that adding exogenous LPA to hepatocyte culture conditions prior to hypothermic ischemia induction can rescue cell viability from preservation injury. We also observed cytotoxicity with low concentrations (0.1%) of bovine serum albumin (BSA), which is known to avidly bind and hold these lipid growth factors. Inhibition of S1P synthesis via selective pharmacological inhibition of sphingosine kinase 2 (SphK2) produced striking results (figure 1). In vitro, cell viability was significantly decreased upon SphK2 inhibition, and in vivo, rodents receiving a liver transplant after that liver was flushed with a solution containing a SphK2 inhibitor had 100% mortality, relative to only 20% control mortality. These data support the hypothesis that serum‐derived lipid signaling molecules, such as LPA and S1P, are protective during hypothermic ischemia, and removing these at the time of organ preservation and flushing may be harmful.Support or Funding InformationNIH R01 DK087737DoD W81XWH‐16‐2‐0040DoD W80XWH‐17‐1‐0602This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.