Lipolytic Mechanisms of PPAR Activation

PPAR 激活的脂肪分解机制

• 批准号: 7160569
• 负责人: JORGE PLUTZKY
• 金额: $ 39.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160569
• 关键词: 2,4-thiazolidinedione; Address; Agonist; Atherosclerosis; Biochemical; Biology; Blood Vessels; Catalysis; Cell Nucleus; Cells; Clinical; Condition; Data; Diabetes Mellitus; Disease; Distal; Dyslipidemias; Endothelial Cells; Enzymes; Fatty Acids; Fatty acid glycerol esters; Fibrates; Gene Targeting; Generations; Genetic; Glucose; Goals; Heterogeneity; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ligands; Link; Lipase; Lipids; Lipolysis; Lipoproteins; Measures; Mediating; Mediator of activation protein; Metabolic Diseases; Metabolism; Methods; Modeling; Monoglycerides; Mus; Muscle; Nature; Nuclear Receptors; Obesity; PPAR alpha; PPAR delta; PPAR gamma; Pathology; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phospholipase A2; Physiological; Plasma; Protein Isoforms; Protein Overexpression; Range; Regulation; Reporting; Research Personnel; Role; Sampling; Signaling Molecule; Starvation; Testing; Thiazolidinediones; Transcriptional Regulation; Triglycerides; Variant; Very low density lipoprotein; Work; blood glucose regulation; concept; extracellular; fatty acid transport; gain of function; hepatic lipase; improved; in vivo; insight; lipid biosynthesis; lipid metabolism; lipoprotein lipase; loss of function; mouse model; novel; programs; research study; response; sensor; uptake

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：过氧化物酶体增殖物激活受体（PPAR）是配体激活的核受体，对于脂肪生成、葡萄糖控制和脂质代谢的转录调节至关重要。最近的工作确定了 PPAR 在脉管系统（包括内皮细胞 (EC)）中的表达和作用。尽管取得了这些进展，但尚未解决的主要问题仍然存在。 PPAR 领域尚未解答的一个核心问题是内源性 PPAR 配体的性质，它可能概括了合成 PPAR 激动剂的作用，或者这种天然介质在生理条件下是如何产生的。同样，尽管大量研究表明 PPAR 在脂质生物学中的作用，但有关脂质代谢途径和随后的 PPAR 激活之间联系的数据却很少。这种见解可能对代谢紊乱和动脉粥样硬化产生重大影响。 数据显示，脂蛋白脂肪酶 (LPL)（富含甘油三酯的脂蛋白代谢中的中心酶）是 PPARα 激活的内源性机制。使用功能获得（LPL 过度表达）和功能丧失（PPARα 缺乏）模型的体外和体内证据支持了这一说法。 LPL 介导的 PPAR-α 激活独立于 LPL 已知的非酶促作用，并且对 PPAR (PPARα>>PPARδ> PPARgamma)、脂蛋白底物 (VLDL>>LDL>HDL) 和测试的其他脂肪酸释放脂肪酶不存在的脂肪酶具有选择性。此外，单酰基甘油 (MAG) 是一种 LPL 特异性产物，被认为是一种有助于这些 LPL 反应的新型 PPARα 激活剂。我们的中心假设是脂肪分解是内源性 PPAR 激活的主要途径，其远端效应由脂蛋白底物、脂肪酶和靶向 PPAR 的不同性质决定。该提案概述了通过这些相同参数定义 PPAR 激活脂肪分解机制的实验。正如初步数据所示，将研究 LPL 介导的 PPARα 激活的独特贡献者，包括 MAG 作为一种研究较少的信号分子和配体传递机制。脂蛋白底物和其他甘油三酯脂肪酶的关键脂肪分解变量将根据其 PPARα、-δ 和 -γ 效应进行检查。这些研究包括对来自小鼠和人类的现有良好表征的 VLDL 和血浆样本的脂解 PPAR 反应进行测量。小鼠模型和人类中存在 LPL 基因变异，具有一系列 LPL 活性，将在体外和体内利用来确定分级的 LPL 功能如何改变已确定的 PPAR 反应。这些 LPL 模型包括通过瞬时 LPL 表达拯救的致命的 LPL 缺陷小鼠。通过这些计划性的努力，我们将深入了解脂肪分解作为选择性内源性 PPAR 激活的机制及其远端转录效应。

项目成果

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.

• DOI: 10.1016/j.jacc.2008.04.055
• 发表时间: 2008-09-02
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Orasanu, Gabriela;Ziouzenkova, Ouliana;Devchand, Pallavi R.;Nehra, Vedika;Hamdy, Osama;Horton, Edward S.;Plutzky, Jorge
• 通讯作者: Plutzky, Jorge