Project 1 - Role of Bilirubin in Protection against Cardiometabolic Syndrome in Obesity

项目I -胆红素在预防心脏代谢中的作用 肥胖综合征 项目概要/摘要 肥胖是心血管代谢疾病的重要诱因，包括高血压、非酒精性脂肪肝、 NAFLD和II型糖尿病。所有这些情况都增加了发病率， 肥胖的死亡率。大规模人群研究表明， 胆红素水平与心血管疾病和代谢性疾病（包括NAFLD和 II型糖尿病。尽管有这些相关的研究，胆红素保护的机制， 心脏代谢疾病尚不清楚。我们有令人兴奋的数据首次证明胆红素 通过核激素受体如过氧化物酶体增殖物激活受体（PPAR-A）的信号， 防止心脏代谢紊乱。此外，胆红素还可抑制糖原合成酶激酶-3（glycogen synthase kinase-3， (GSK3增加PPAR γ靶基因，如成纤维细胞生长因子21（FGF 21）;然而， GSK 3 β失活/PPAR β活化在抗高血压、抗脂肪变性和抗糖尿病作用中的作用 中度高胆红素血症的发病率尚不清楚。胆绿素还原酶（BVR）是负责 胆绿素还原为胆红素。它可以产生血浆中发现的胆红素，并在细胞内产生。 本提案的目的是检验胆红素和BVRA预防肥胖的中心假设- 通过激活过氧化物酶体增殖物激活物受体（PPAR）信号传导轴诱导肝脂肪变性、胰岛素抵抗和高血压。目的 1将检验胆红素治疗引起的慢性中度高胆红素血症或 肝UGT 1A 1拮抗作用可降低血压并逆转饮食性肥胖诱导的肝脂肪变性 和肝脏胰岛素抵抗。目的2将检验中度高胆红素血症降低血液流变学的假设。 压力和逆转肝脂肪变性和胰岛素抵抗通过激活的过氧化物酶体增殖物激活受体。目标3将测试 肝胆红素生成特异性缺失增强肝脂肪变性和胰岛素的假说 通过GSK 3介导的途径降低PPAR γ活性来抵抗。这些研究的结果将 对中度高胆红素血症的发展具有深远的意义， 肥胖引起的心脏代谢疾病这些研究也将确定胆红素作为一种新的作用， 核激素受体信号分子和这种机制在预防肥胖中的作用- 诱发的心脏代谢疾病，如高血压、NAFLD和II型糖尿病。

PROJECT I – ROLE OF BILIRUBIN IN PROTECTION AGAINST CARDIOMETABOLIC SYNDROME IN OBESITY PROJECT SUMMARY/ABSTRACT Obesity is a significant contributor to cardiometabolic diseases including hypertension, non-alcoholic fatty liver disease (NAFLD) and type II diabetes. All of these conditions contribute to the increased morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and development of cardiovascular disease and metabolic disorders including NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against cardiometabolic disease is not known. We have exciting data demonstrating for the first time that bilirubin signals through nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPAR) to protect against cardiometabolic disorders. In addition, bilirubin can also inactivate glycogen synthase kinase-3 (GSK3) to increase PPAR target genes such as fibroblast growth factor 21 (FGF21); however, the specific roles of GSK3 inactivation/PPAR activation to the anti-hypertensive, anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia are not known. Biliverdin reductase (BVR) is the enzyme responsible for reduction of biliverdin to bilirubin. It can generate bilirubin found in the plasma and generated inside the cell. The goal of this proposal is to test the central hypothesis that bilirubin and BVRA protect against obesity- induced hepatic steatosis, insulin resistance and hypertension via activation of the PPARsignaling axis. Aim 1 will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 lowers blood pressure and reverses dietary obesity-induced hepatic steatosis and hepatic insulin resistance. Aim 2 will test the hypothesis that moderate hyperbilirubinemia lowers blood pressure and reverses hepatic steatosis and insulin resistance via activation of PPAR. Aim 3 will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3mediated pathway that decreases PPAR activity. Findings of these studies will have profound implications on development of moderate hyperbilirubinemia as a novel therapy for treatment of obesity-induced cardiometabolic disease. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in protection against obesity- induced cardiometabolic diseases such as hypertension, NAFLD and type II diabetes.