Modulation of Endogenous PPAR Activation

过氧化物酶体增殖物激活受体(PPAR)是配体激活的转录因子，调节 许多关键的代谢途径。对PPAR的许多见解来自于对合成PPAR的研究 激动剂，包括临床使用的那些。PPARa被降脂的贝特类激活，调节脂肪酸 新陈代谢。由胰岛素敏感型噻唑烷二酮激活的PPARy控制脂肪生成和血糖 动态平衡。PPARa和PPARy的激活都可以限制动脉粥样硬化和炎症。这具身体 合成激动剂激活PPAR的数据证实了理解内源性的重要性 PPAR激活。尽管如此，内源性PPAR调节的本质仍然知之甚少。 最近，我们报道了脂蛋白脂酶(LPL)对循环中的脂蛋白具有特异性和选择性的作用。 生成PPARa配体的方式。这一建议侧重于中心假设，即直接和 内源性PPAR拮抗的间接途径在决定 代谢反应。提供了三种不同的内生途径的数据，这三种途径可能对 调节PPAR活性。这些机制将通过研究它们对已建立的 PPAR激活的体外和体内模型。 LPL介导的PPARa激活提示不同结构的脂肪酸对内皮的影响 可能是由于不同的PPARa激活，包括拮抗。在Aim 1中，PPAR的激活和抑制 通过特定的脂肪酸将在体外和体内进行研究，将omega-3脂肪酸与饱和和 反式脂肪酸。肝脏核因子4α(HNF4a)是一种知之甚少但被激活的关键脂肪酸 调节脂肪代谢、血栓形成和血糖控制的受体。通过使用 在我们的LPL/PPARa研究中，我们发现了新的脂代谢操作 HNF4a的调控机制及PPARa和HNF4a对HNF4a信号通路的分化反应 脂类代谢。在目标2中，将探索HNF4a和PPARa之间的这种差异。一本小说但是 直接内源性PPAR拮抗剂的存在可能是PPAR调控的重要机制。 虽然β胡萝卜素的对称切割产生了RXR核受体的天然配体，但我们有 发现不对称的β-胡萝卜素裂解会产生一种特定的载脂胡萝卜素，直接对抗 PPAR响应。在目标3中，这种直接拮抗剂将在体外和体内进行表征。加在一起，这些 研究结合了生化、生物和体内模型，以更好地了解内源性调节如何 PPAR活性的高低可能决定生物反应。

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.