Integrative Role of Bilirubin on Obesity

摘要 肥胖是非酒精性脂肪性肝病(NAFLD)和II型糖尿病的主要原因。这两个都是 疾病是肥胖症发病率和死亡率的重要因素。大量的人口研究已经 血清胆红素水平与非酒精性脂肪肝和II型脂肪肝的发生呈负相关 糖尿病。尽管有这些相关的研究，胆红素预防NAFLD的机制和类型 II型糖尿病尚不清楚。我们有令人兴奋的数据第一次证明胆红素也是一种信号 能够通过核激素受体(如PPARpha)传递信号的分子此外，胆红素还可以灭活糖原合成酶激酶-3β(GSK3Beta)以 增加PPARpha靶基因，如成纤维细胞生长因子21(FGF21)；然而，特定的作用 GSK3Beta失活/PPARpha激活对Medium的抗脂变和抗糖尿病作用 高胆红素血症尚不清楚。胆绿素还原酶(BVR)是一种负责还原 胆绿素转化为胆红素。它可以产生血浆中发现的胆红素以及体内产生的胆红素。 牢房。该提案的目标是检验胆红素和BVRA预防疾病的中心假设 肥胖通过激活PPARpha信号轴导致肝脏脂肪变性和胰岛素抵抗。目标1 该提案将检验一种假设，即胆红素治疗导致的慢性中度高胆红素血症 拮抗肝脏UGT1A1可逆转饮食性肥胖所致的肝脏脂肪变性和肝脏胰岛素 抵抗。该提案的目标2将检验中度高胆红素血症逆转肝脏的假设 脂肪变性和通过激活PPARα产生的胰岛素抵抗。提案的目标3将检验这样的假设： 肝脏胆红素生成的特异性丢失通过一种 GSK3Beta介导了降低PPARpha活性的途径。建议中概述的研究结果将 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 治疗肥胖所致的NAFLD和胰岛素抵抗。这些研究还将确定 胆红素作为核激素受体信号分子及其在保护中的作用 抗肥胖所致的NAFLD和胰岛素抵抗。

Abstract Obesity is the leading cause of non-alcoholic fatty liver disease (NAFLD) and type II diabetes. Both of these conditions contribute to the morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against NAFLD and type II diabetes is not known. We have exciting data demonstrating for the first time that bilirubin is also a signaling molecule capable of signaling through the nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPARalpha) In addition, bilirubin can also inactivate glycogen synthase kinase-3Beta (GSK3Beta) to increase PPARalpha target genes such as fibroblast growth factor 21 (FGF21); however, the specific role of GSK3Beta inactivation/PPARalpha activation to the anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia is not known. Biliverdin reductase (BVR) is the enzyme responsible for the reduction of biliverdin to bilirubin. It can generate bilirubin that is found in the plasma as well as bilirubin 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 and insulin resistance via activation of the PPARalpha signaling axis. Aim 1 of the proposal will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 can reverse dietary obesity induced hepatic steatosis and hepatic insulin resistance. Aim 2 of the proposal will test the hypothesis that moderate hyperbilirubinemia reverses hepatic steatosis and insulin resistance via activation of PPARalpha. Aim 3 of the proposal will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3Beta mediated pathway that decreases PPARalpha activity. Findings of the studies outlined in the proposal will have profound implications on the development of moderate hyperbilirubinemia as a novel therapy for the treatment of obesity induced NAFLD and insulin resistance. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in the protection against obesity induced NAFLD and insulin resistance.