Antioxidant-PPARalpha interaction and hypertension

描述(申请人提供)：肥胖是一个主要的公共卫生问题，已导致全球流行，也是糖尿病、动脉粥样硬化和心血管疾病的根本原因。内脏脂肪和皮下脂肪过多预示着血管疾病和相关并发症，包括血管功能障碍、胰岛素抵抗和脂肪燃烧核受体过氧化体增殖物激活受体α(PPARα)水平下降。除了PPARα调节脂肪酸代谢外，它还在血管炎症和动脉粥样硬化中具有抗炎特性，很可能是通过诱导脂联素来实现的。脂联素是一种脂肪特异性激素，具有抗炎和血管保护作用，肥胖时其循环水平会降低。肥胖通过增加活性氧来增加氧化应激，同时降低关键细胞保护系统的表达和活性，包括血红素加氧酶(HO)、胆红素和PPARα，同时增加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，炎性脂肪因子如肿瘤坏死因子α、IL-1和IL-6增加)可能导致血管功能障碍，这是血管疾病和高血压的前奏。在这里，我们提供了胆红素激活PPARα活性的新数据，这可能是一种内源性配体激动剂。我们假设，胆红素、PPARα和脂联素这三个保护因子是密不可分的，它们形成了一个功能模块，而脂肪细胞中这些因子中的任何一个的缺失都会导致脂肪细胞和血管功能障碍，这与肥胖有关。我们将在体外和体内测试这一模型，以表明胆红素具有保护减肥和抗糖尿病特性，这些特性是由PPARα介导的，可以减少血管功能障碍。

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.