Fish oil protects the liver from parenteral nutrition-induced injury via GPR120-mediated PPARγ signaling

Intravenous fish oil lipid emulsions (FOLE) can prevent parenteral nutrition (PN)-induced liver injury in murine models and reverse PN-induced cholestasis in pediatric patients. However, the mechanisms by which fish oil protects the liver are incompletely characterized. Fish oil is rich in omega-3 fatty acids, which are ligands for the G-protein coupled receptor 120 (GPR120), expressed on hepatic Kupffer cells. This study tested the hypothesis that FOLE protects the liver from PN-induced injury through GPR120 signaling. Utilizing a previously described murine model of PN-induced liver injury in which mice develop steatosis in response to an oral parenteral nutrition diet, FOLE was able to preserve normal hepatic architecture in wild type mice, but not in congenic GPR120 knockout (gpr120- / -) mice. To further characterize the requirement of intact GPR120 for FOLE-mediated hepatic protection, gene expression profiles of key regulators of fat metabolism were measured. PPAR gamma was identified as a gene that is up-regulated by the PN diet and normalized with the addition of FOLE in wild type, but not in gpr120- / - mice. This was confirmed at the protein expression level. A PPAR gamma expression array further identified CD36 and SCD1, both down-stream effectors of PPAR gamma, to be up-regulated in PN-fed wild type mice yet normalized upon FOLE administration in wild type but not in gpr120- / - mice. Together, these results suggest that FOLE protects the liver, in part, through activation of GPR120 and the downstream effectors PPAR gamma and CD36. Identification of key genetic determinants of FOLE-mediated hepatic protection may provide targets for small molecule-based hepatic protection strategies.