Abstract 582: A Novel PPARδ-Hepatic Lipase Transcriptional Pathway
PPARδ is a fatty acid responsive transcription factor that critically regulates lipid metabolism, energy balance and atherosclerosis. Despite extensive characterization of PPARδ responses induced by pharmacologic agents, the identity of endogenous ligands for PPAR activation remains a central unresolved issue in this field. We have previously identified that lipoprotein lipase (LPL) hydrolysis of VLDL and endothelial lipase (EL) hydrolysis of HDL can liberate PPARδ activators and regulate PPARδ responsive genes in a selective manner. This working model implicates lipoprotein metabolism as a putative source for PPAR activation. Hepatic Lipase (HL) is a third member of this triacylglycerol lipase family that regulates both HDL and VLDL metabolism. We hypothesized that HL also activates PPAR transcriptional responses. Here, we report a novel role for HL in PPAR transcription by demonstrating that HL activates PPARδ through hydrolysis of VLDL. Employing a PPAR-LBD/GAL-4 luciferase heterologous transcriptional reporter system, we demonstrate that HL activated PPARδ selectively, with miminal PPARδ activation and no PPARδ activation. In light of HL’s known phospholipase and triglyceride hydrolase activity, we next determined the role of HDL and VLDL in HL-mediated PPARδ activation. We found that VLDL is the preferred substrate for this HL/PPARδ pathway. In addition, heparin, an established activator of HL, markedly augmented HL-mediated activation of PPARδ, and pre-treatment of cells with tetrahydrolipstatin, a general lipase inhibitor, abrogated HL-mediated PPARδ stimulation. Finally, we have demonstrated that HL mediated VLDL hydrolysis enhances PLTP gene expression, a known PPARδ target. Taken together these data identify a novel pathway for PPARδ transcriptional activation through HL-mediated VLDL hydrolysis and implicate PPARδ as a central integrator of lipoprotein metabolism.