Abstract
BackgroundPPARs (α,γ,δ) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Methods/Principal FindingsUsing PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL≫LDL, IDL) to activate PPARδ preferentially over PPARα or PPARγ, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARδ in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARδ target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARδ activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARδ activation and ADRP gene regulation in vitro.ConclusionsThese data define a novel pathway involving HL hydrolysis of VLDL that activates PPARδ through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.
Highlights
Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in energy balance [1]
By integrating this data with a global metabolite profiling approach, we found that VLDL hydrolysis by hepatic lipase (HL) generates specific unsaturated fatty acid (FA) that can induce canonical PPARd dependent transcriptional responses in vitro and in vivo, with functional effects on cellular lipid droplet formation in hepatocytes
Hepatic Lipase uses VLDL preferentially to activate PPARd Standard PPAR ligand binding domain (LBD) assays for all three human PPAR isoforms were performed in hepatic lipase (HL)-transfected 293 cells stimulated with HDL, IDL, LDL and VLDL at the concentrations shown
Summary
Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in energy balance [1]. Three PPAR isotypes – alpha (a), beta/ delta (b/d), and gamma (c)- are expressed in metabolically active tissues as well as vascular and inflammatory cells [2,3]. Genetic models and studies with synthetic PPAR agonists reveal key but distinct functions for PPARa and PPARd in regulating fatty acid (FA) metabolism in muscle and liver, whereas PPARc is a critical determinant of adipose tissue differentiation [4]. PPARs (a,c,d) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown
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