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

项目I--胆红素对心脏代谢的保护作用 肥胖综合征 项目摘要/摘要 肥胖是心脏代谢性疾病的一个重要因素，包括高血压、非酒精性脂肪肝 非酒精性脂肪肝(NAFLD)和II型糖尿病。所有这些情况都会增加发病率和 肥胖的死亡率。大量的人群研究表明，血清与 胆红素水平与非酒精性脂肪肝等心血管疾病和代谢紊乱的发生 二、糖尿病。尽管有这些相关的研究，但胆红素预防疾病的机制 心脏代谢性疾病尚不清楚。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)来传递信号 预防心脏新陈代谢障碍。此外，胆红素还可以灭活糖原合成酶-3 (GSK3)增加PPAR靶基因，如成纤维细胞生长因子21(FGF21)；然而，特异性 GSK3失活/PPAR激活在抗高血压、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情况尚不清楚。胆绿素还原酶(BVR)是负责 胆绿素还原为胆红素。它可以产生在血浆中发现的、在细胞内产生的胆红素。 这项提案的目的是验证核心假设，即胆红素和BVRA可以预防肥胖。 通过激活PPAR信号轴诱导肝脏脂肪变性、胰岛素抵抗和高血压。目标 1将检验由胆红素治疗引起的慢性中度高胆红素血症或 肝脏UGT1A1拮抗剂降低血压和逆转饮食肥胖所致的肝脏脂肪变性 和肝脏胰岛素抵抗。目标2将检验以下假设：中度高胆红素血症可降低血液 并通过激活PPAR逆转肝脏脂肪变性和胰岛素抵抗。目标3将测试 假设肝脏胆红素生成的特异性丢失会加剧肝脏脂肪变性和胰岛素 通过Gsk3介导的降低PPAR活性的途径产生抗性。这些研究的结果将 对中度高胆红素血症作为一种新的治疗方法的发展具有深远的意义 肥胖引起的心脏代谢性疾病。这些研究还将确定胆红素作为一种 核激素受体信号分子及其在预防肥胖中的作用 诱发心脏代谢性疾病，如高血压、非酒精性脂肪肝和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.