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，是掺杂，葡萄糖控制和脂质代谢的转录调节的核心。最近的工作在包括内皮细胞（EC）在内的脉管系统中建立了PPAR的表达和作用。尽管有这些进展，但主要未解决的问题仍然存在。 PPAR领域中的一个中心未解决的问题是内源性PPAR配体的性质，它可能会概括合成PPAR激动剂的作用，或者在生理条件下如何产生这种天然介体。同样，尽管大量研究涉及脂质生物学中的PPAR，但关于脂质代谢途径与随后的PPAR激活之间的联系的数据很少。这种洞察力可能对代谢性疾病和动脉粥样硬化具有重大影响。 介绍了数据，以建立脂蛋白脂肪酶（LPL），这是富含甘油三酸酯的脂蛋白代谢中的中心酶，作为PPARALPHA激活的内源性机制。在体外和体内证据，使用功能增长（LPL过表达）和功能丧失（PPARALPHA缺陷）模型，都支持这一主张。 LPL介导的PPAR-Alpha激活与LPL的已知非酶作用无关，并且对PPAR（PPARALPHA >> PPARDELTA> PPARGAMMA）具有选择性，脂蛋白底物（VLDL >> LDL> HDL）和其他脂肪酶 - 不适合其他脂肪酸酸酸解液（lipase-bess）。此外，LPL特异性产品单酰甘油（MAG）被确定为有助于这些LPL响应的新型PPARALPHA激活剂。我们的中心假设是脂解是内源性PPAR激活的主要途径，其远端作用由脂蛋白底物，脂肪酶和靶向PPAR的不同性质确定。该提案概述了定义涂脂解的实验，以跨这些相同的参数激活PPAR。如初步数据所建议的那样，将研究LPL介导的PPARALPHA激活的独特贡献者，包括MAG作为少量研究的信号分子和配体递送的机制。将根据其pParalpha，-delta和-gamma效应检查脂蛋白底物和其他Tiglyceride脂肪酶的关键脂解变量。这些研究包括对来自小鼠和人类的可用特征良好的VLDL和等离子体样品的脂溶剂PPAR响应的度量。在小鼠模型和人类中具有一系列LPL活性的遗传LPL变体的存在，将在体外和体内使用，以确定分级LPL功能如何改变良好的PPAR响应。这些LPL模型包括瞬时LPL表达救出的其他致命LPL缺陷小鼠。通过这些程序化的努力，洞察力将获得脂肪分解，作为选择性内源性PPAR激活及其远端转录效应的一种机制。

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