Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated nuclear receptors central to the transcriptional regulation of adipogenesis, glucose control and lipid metabolism. More recent work establishes PPAR expression and effects in the vasculature, including endothelial cells (EC). Despite these advances, major unresolved issues persist. One central unanswered question in the PPAR field is the nature of endogenous PPAR ligands, which might recapitulate the effects of synthetic PPAR agonists, or how such natural mediators are produced under physiologic conditions. Similarly, despite extensive studies implicating PPARs in lipid biology, little data exists regarding the links between pathways of lipid metabolism and subsequent PPAR activation. Such insight could have major implications for metabolic disorders and atherosclerosis. Data is presented establishing lipoprotein lipase (LPL), the central enzyme in triglyceride-rich lipoprotein metabolism, as an endogenous mechanism for PPARalpha activation. In vitro and in vivo evidence, using both gain of function (LPL overexpression) and loss of function (PPARalpha-deficiency) models, support this claim. LPL-mediated PPAR-alpha activation is independent of LPL's known non-enzymatic effects and is selective as to PPAR (PPARalpha>>PPARdelta> PPARgamma), lipoprotein substrate (VLDL>>LDL>HDL), and lipase- absent with other fatty acid-releasing lipases tested. Furthermore, monoacylglycerol (MAG), a LPL-specific product, is identified as a novel PPARalpha activator contributing to these LPL responses. Our central hypothesis is that lipolysis is a major pathway for endogenous PPAR activation, with distal effects determined by the varying nature of lipoprotein substrate, lipase, and targeted PPAR. This proposal outlines experiments to define lipolytic mechanisms for PPAR activation across these same parameters. Unique contributors to LPL-mediated PPARalpha activation, as suggested by preliminary data, will be studied, including MAG as a little studied signaling molecule and mechanisms of ligand delivery. Key lipolytic variables of lipoprotein substrate and other tiglyceride lipases will be examined in terms of their PPARalpha, -delta, and -gamma effects. These studies include measures of lipolytic PPAR responses on available well-characterized VLDL and plasma samples from both mice and humans. The existence of genetic LPL variants in mouse models and in humans, which have a range of LPL activity, will be utilized in vitro and in vivo to determine how graded LPL function alters well-established PPAR responses. These LPL models include the otherwise lethal LPL-deficient mice rescued by transient LPL expression. Through these programmatic efforts, insight will be gained into lipolysis as a mechanism for selective endogenous PPAR activation, and its distal transcriptional effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071745-02
Application #
6838154
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$416,874
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Tatematsu, Satoru; Francis, Sanjeev A; Natarajan, Pradeep et al. (2013) Endothelial lipase is a critical determinant of high-density lipoprotein-stimulated sphingosine 1-phosphate-dependent signaling in vascular endothelium. Arterioscler Thromb Vasc Biol 33:1788-94
Brown, Jonathan D; Oligino, Eric; Rader, Daniel J et al. (2011) VLDL hydrolysis by hepatic lipase regulates PPAR? transcriptional responses. PLoS One 6:e21209
Ruby, Maxwell A; Goldenson, Benjamin; Orasanu, Gabriela et al. (2010) VLDL hydrolysis by LPL activates PPAR-alpha through generation of unbound fatty acids. J Lipid Res 51:2275-81
Kanda, Takeshi; Brown, Jonathan D; Orasanu, Gabriela et al. (2009) PPARgamma in the endothelium regulates metabolic responses to high-fat diet in mice. J Clin Invest 119:110-24
Orasanu, Gabriela; Plutzky, Jorge (2009) The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol 53:S35-42
Orasanu, Gabriela; Ziouzenkova, Ouliana; Devchand, Pallavi R et al. (2008) The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 52:869-81
Mazzone, Theodore; Chait, Alan; Plutzky, Jorge (2008) Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371:1800-9
Ziouzenkova, Ouliana; Orasanu, Gabriela; Sharlach, Molly et al. (2007) Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med 13:695-702
Zandbergen, Fokko; Plutzky, Jorge (2007) PPARalpha in atherosclerosis and inflammation. Biochim Biophys Acta 1771:972-82
Ahmed, W; Ziouzenkova, O; Brown, J et al. (2007) PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J Intern Med 262:184-98

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