PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome

Abstract Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid binding protein that transports phosphatidylcholine (PC) between cellular membranes. PC-TP knockout mice are more sensitive to glucose and insulin, have increased beta oxidation and improved liver health compared to wild-type mice. To better understand the protective metabolic effects associated with PC-TP deletion, we investigated how hepatic PC-TP affects lipid metabolism, sensitivity to glucose and insulin, and energy homeostasis in a mouse model of diet-induced obesity. We generated a liver-specific PC-TP knockout mouse (L-Pctp-/-), which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high fat diet. Hepatic deletion of PC-TP also reduces levels of triglycerides and phospholipids in skeletal muscle, suggesting that PC-TP in the liver influences lipid metabolism in the muscle. Gene expression analyses suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a novel, direct interaction between PC-TP and PPARδ that was not observed for other PPAR family members. We confirmed the PC-TP-PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer combined with a reduction of exogenously supplied lipids through serum starvation relieves PC-TP mediated PPAR repression. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.