Modulation of Endogenous PPAR Activation

内源性 PPAR 激活的调节

• 批准号: 7029362
• 负责人: JORGE PLUTZKY
• 金额: $ 38.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029362
• 关键词: diabetic angiopathy; fatty acids; human tissue; laboratory mouse; lipid metabolism; lipoprotein lipase; omega 3 fatty acid; peroxisome proliferator activated receptor; saturated fatty acids; vascular endothelium

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors regulating many key metabolic pathways. Much of the insight into PPARs derives from studies with synthetic PPAR agonists, including those in clinical use. PPARa, activated by lipid-lowering fibrates, regulates fatty acid metabolism. PPARy, activated by insulin-sensitizing thiazolidinediones, controls adipogenesis and glucose homeostasis. Both PPARa and PPARy activation may limit atherosclerosis and inflammation. This body of data for PPAR activation by synthetic agonists establishes the importance of understanding endogenous PPAR 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 selective manner to generate PPARa ligands. This proposal focuses on the central hypothesis that direct and indirect pathways for endogenous PPAR antagonism play an important part in determining metabolic responses. Data is provided for three different endogenous pathways that may negatively regulate PPAR activity. These mechanisms will be studied by examining their modulation of well-established in vitro and in vivo models of PPAR activation. LPL-mediated PPARa activation suggests the discrepant endothelial effects of structurally diverse fatty acids may be due to differential PPARa activation, including antagonism. In Aim 1, PPAR activation and inhibition by specific fatty acids will be studied in vitro and in vivo, contrasting omega-3 fatty acids to saturated and trans-fatty acids. Hepatic nuclear factor 4 alpha (HNF4a) is a poorly understood but critical fatty acidactivated receptor that regulates lipid metabolism, thrombosis, and glucose control. By using the manipulations of lipid metabolism employed in our LPL/PPARa studies, we have identified novel mechanisms of HNF4a modulation and divergent responses between PPARa and HNF4a to pathways of lipid metabolism. In Aim 2, this divergence between HNF4a and PPARa will be explored. A novel but powerful 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 have identified that asymmetric beta carotene cleavage produces a specific apocarotenal that directly antagonizes PPAR responses. In Aim 3, this direct antagonist will be characterized in vitro and in vivo. Together, these studies integrate biochemical, biologic, and in vivo models to better understand how endogenous modulation of PPAR activity may determine biologic responses.

过氧化物酶体增殖物激活受体（PPARs）是配体激活的转录因子，其调节 许多关键的代谢途径。对PPARs的许多了解来自于对合成PPARs的研究 激动剂，包括临床使用的激动剂。PPARa，由降脂贝特类激活，调节脂肪酸 新陈代谢.由胰岛素增敏噻唑烷二酮激活的PPARy控制脂肪生成和葡萄糖 体内平衡PPARa和PPARy激活都可以限制动脉粥样硬化和炎症。这个身体 合成激动剂激活过氧化物酶体增殖物激活物的数据确立了理解内源性 过氧化物酶体增殖物激活体。尽管如此，内源性PPAR调节的性质仍然知之甚少。 最近，我们报道脂蛋白脂酶（LPL）以一种特异性和选择性的方式作用于循环脂蛋白， 产生PPARa配体的方式。这一建议的重点是中心假设，直接和 内源性PPAR拮抗作用的间接途径在决定 代谢反应提供了三种不同的内源性途径的数据， 调节PPAR活性。这些机制将通过检查它们对已建立的 在体外和体内模型的过氧化物酶体增殖物激活受体活化。 LPL介导的PPARa活化表明结构不同的脂肪酸对内皮细胞的作用不同 可能是由于PPARa的不同活化，包括拮抗作用。在目标1中， 将在体外和体内研究特定脂肪酸，将omega-3脂肪酸与饱和和 反式脂肪酸。肝核因子4 α（HNF 4a）是一种了解不多但关键的脂肪酸激活的 调节脂质代谢、血栓形成和葡萄糖控制的受体。通过使用 在我们的LPL/PPARa研究中使用的脂质代谢的操作，我们已经鉴定了新的 HNF 4a的调节机制以及PPARa和HNF 4a之间对HNF 4a调节途径的不同反应。 脂质代谢在目标2中，将探索HNF 4a和PPARa之间的这种差异。小说，但 PPAR调节的强有力机制是存在直接内源性PPAR拮抗剂。 虽然β-胡萝卜素的对称裂解产生了RXR核受体的天然配体，但我们发现， 发现不对称β-胡萝卜素裂解产生一种特异性的脱胡萝卜素醛， PPAR反应。在目的3中，将在体外和体内表征该直接拮抗剂。所有这些 研究整合了生物化学、生物学和体内模型，以更好地了解内源性调节 可能决定生物反应。