Antioxidant-PPARalpha interaction and hypertension

抗氧化剂-PPARα 相互作用与高血压

基本信息

批准号：
8968860
负责人：
Terry D Hinds
金额：
$ 15.42万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-15 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968860
关键词：
Adipocytes Adipose tissue Adult Affect Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Anus Atherosclerosis Attenuated Bilirubin Biliverdin reductase Biliverdine Binding Blood Vessels Burn injury Cardiovascular Diseases Cardiovascular system Central obesity Clinical Clinical Management Data Development Diabetes Mellitus Diastolic blood pressure Diet Epidemic Event Fatty acid glycerol esters Functional disorder Gilbert Disease Glucose Health Expenditures Heme Homeostasis Hormonal Hormones Hyperbilirubinemia Hypertension Individual Inflammatory Insulin Insulin Resistance Interleukin-1 Interleukin-6 Knowledge Lead Ligands Link Lipids Mediating Medical Metabolic syndrome Molecular Nonesterified Fatty Acids Nuclear Receptors Obese Mice Obesity Outcome Overweight Oxidative Stress Oxygenases PPAR alpha Plasma Population Production Property Proteins Public Health Reactive Oxygen Species Regulator Genes Research Resistance Risk Factors Serum Signal Transduction System TNF gene Testing Tissue Expansion Vascular Diseases Visceral adipokines adiponectin base cost cytokine diabetic fatty acid metabolism glucose uptake humanized mouse in vitro Model in vivo lipid biosynthesis mouse model novel prevent response subcutaneous vascular endothelial dysfunction vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major public health concern that has led to a worldwide epidemic and is the underlying cause of diabetes, atherosclerosis and cardiovascular disease. Excessive visceral and subcutaneous fat is predictive of vascular disease and associated complications, including vascular dysfunction, insulin resistance and decreased levels of the fat burning nuclear receptor, peroxisome proliferator-activated receptor α (PPARα). In addition to PPARα regulating fatty acid metabolism, it has anti-inflammatory properties in vascular inflammation and atherosclerosis, most likely through induction of adiponectin. Adiponectin is an adipose- specific hormone with anti-inflammatory and vascular protective properties, and its circulating levels are decreased in obesity. Obesity increases oxidative stress by enhancing reactive oxygen species and simultaneously decreases expression and activity of key cytoprotective systems including heme oxygenase (HO) and bilirubin as well as PPARα, while increasing inflammatory cytokines and insulin resistance. These consequences of obesity-mediated adipocyte dysfunction (decreased PPARα/adiponectin and increased inflammatory adipokines such as TNFα, IL-1 and IL-6) may lead to vascular dysfunction, which is a prelude to vascular disease and hypertension. Here we provide novel data that bilirubin activates PPARα activity, which may function as an endogenous ligand agonist. We hypothesize that the three protective factors, bilirubin, PPARα and adiponectin, are inextricably linked forming a functional module and a deficiency in any of these factors within adipocytes leads to adipocyte and vascular dysfunction that is associated with obesity. We will test this model in vitro and in vivo to show that bilirubin has protective ani-obese and anti- diabetic properties that are mediated by PPARα that reduces vascular dysfunction.

描述（由适用提供）：肥胖是一个主要的公共卫生问题，导致了全球流行病，是糖尿病，动脉粥样硬化和心血管疾病的根本原因。过度的内脏和皮下脂肪可预测血管疾病和相关并发症，包括血管功能障碍，胰岛素抵抗和改善脂肪燃烧核受体的水平，过氧化物体增殖物激活受体α（PPARα）。除了控制脂肪酸代谢的PPARα外，它在血管注射和动脉粥样硬化中具有抗炎特性，最有可能通过诱导脂联素。脂联素是一种具有抗炎和血管保护特性的脂肪特异性激素，肥胖症的循环水平降低。肥胖通过增强活性氧通过增强氧化物应激，并简单地降低了包括血红素加氧酶（HO）和胆红素以及PPARα的关键细胞保护系统的表达和活性，同时增加了炎性细胞因子和胰岛素抵抗。肥胖介导的脂肪细胞功能障碍的这些后果（PPARα/脂联素降低和炎症性脂肪因子增加，例如TNFα，IL-1和IL-6）可能导致血管功能障碍，这是血管疾病和血管疾病和高血压的预序。在这里，我们提供了胆红素激活PPARα活性的新型数据，这可能是内源性配体激动剂。我们假设，胆红素，PPARα和脂联素的三个受保护因素是密不可分的，形成功能模块以及脂肪细胞中任何这些因素的缺乏会导致与肥胖相关的脂肪细胞和血管功能障碍。我们将在体外和体内测试该模型，以表明胆红素保护了由PPARα介导的Ani-Obese和抗糖尿病特性，从而降低了血管功能障碍。