Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors regulatingmany key metabolic pathways. Much of the insight into PPARs derives from studies with synthetic PPARagonists, including those in clinical use. PPARa, activated by lipid-lowering fibrates, regulates fatty acidmetabolism. PPARy, activated by insulin-sensitizing thiazolidinediones, controls adipogenesis and glucosehomeostasis. Both PPARa and PPARy activation may limit atherosclerosis and inflammation. This body ofdata for PPAR activation by synthetic agonists establishes the importance of understanding endogenousPPAR activation. Despite this, the nature of endogenous PPAR modulation remains poorly understood.Recently, we reported lipoprotein lipase (LPL) acts on circulating lipoproteins in a specific and selectivemanner to generate PPARa ligands. This proposal focuses on the central hypothesis that direct andindirect pathways for endogenous PPAR antagonism play an important part in determiningmetabolic responses. Data is provided for three different endogenous pathways that may negativelyregulate PPAR activity. These mechanisms will be studied by examining their modulation of well-establishedin vitro and in vivo models of PPAR activation.LPL-mediated PPARa activation suggests the discrepant endothelial effects of structurally diverse fatty acidsmay be due to differential PPARa activation, including antagonism.
In Aim 1, PPAR activation and inhibitionby specific fatty acids will be studied in vitro and in vivo, contrasting omega-3 fatty acids to saturated andtrans-fatty acids. Hepatic nuclear factor 4 alpha (HNF4a) is a poorly understood but critical fatty acidactivatedreceptor that regulates lipid metabolism, thrombosis, and glucose control. By using themanipulations of lipid metabolism employed in our LPL/PPARa studies, we have identified novelmechanisms of HNF4a modulation and divergent responses between PPARa and HNF4a to pathways oflipid metabolism.
In Aim 2, this divergence between HNF4a and PPARa will be explored. A novel butpowerful mechanism for PPAR modulation would be the existence of a direct endogenous PPAR antagonist.While symmetric cleavage of beta carotene generates natural ligands for the RXR nuclear receptor, we haveidentified that asymmetric beta carotene cleavage produces a specific apocarotenal that directly antagonizesPPAR responses.
In Aim 3, this direct antagonist will be characterized in vitro and in vivo. Together, thesestudies integrate biochemical, biologic, and in vivo models to better understand how endogenous modulationof PPAR activity may determine biologic responses.
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