Integrative Role of Bilirubin on Obesity

胆红素对肥胖的综合作用

基本信息

  • 批准号:
    10337279
  • 负责人:
  • 金额:
    $ 49.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

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.
摘要 肥胖是非酒精性脂肪肝(NAFLD)和II型糖尿病的主要原因。这两 这些条件导致肥胖症的发病率和死亡率。大量的人口研究表明, 表明血清胆红素水平与NAFLD和II型的发展呈负相关, 糖尿病尽管有这些相关的研究,胆红素保护NAFLD和类型的机制, II型糖尿病是未知的。我们有令人兴奋的数据首次证明胆红素也是一种信号, 能够通过核激素受体如过氧化物酶体增殖物激活受体(PPARalpha)发出信号的分子。此外,胆红素还可以使糖原合成酶激酶-3 β(GSK 3 β)活化, 增加PPARalpha靶基因,如成纤维细胞生长因子21(FGF 21);然而, GSK 3 β失活/PPARalpha活化对中度脂多糖抗脂肪变性和抗糖尿病作用的影响 尚不清楚高胆红素血症。胆绿素还原酶(BVR)是负责还原 胆绿素与胆红素的比值。它可以产生胆红素是发现在血浆以及胆红素产生内部 牢房本提案的目的是检验胆红素和BVRA防止 肥胖通过激活PPARalpha信号轴诱导肝脂肪变性和胰岛素抵抗。目标1 该提案将检验胆红素治疗引起的慢性中度高胆红素血症 或拮抗肝脏UGT 1A 1可以逆转饮食性肥胖诱导的肝脂肪变性和肝胰岛素 阻力该提案的目的2将检验中度高胆红素血症逆转肝硬化的假设。 脂肪变性和胰岛素抵抗。该提案的目标3将检验以下假设: 肝胆红素生成的特异性缺失通过以下途径增强肝脂肪变性和胰岛素抵抗: 降低PPARalpha活性的GSK 3 β介导途径。建议中概述的研究结果将 对中度高胆红素血症的发展具有深远的意义,作为一种新的治疗方法, 治疗肥胖诱导的NAFLD和胰岛素抵抗。这些研究也将确定新的作用, 胆红素作为一种核激素受体信号分子及其机制在保护 抗肥胖诱导的NAFLD和胰岛素抵抗。

项目成果

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DAVID E STEC其他文献

DAVID E STEC的其他文献

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{{ truncateString('DAVID E STEC', 18)}}的其他基金

Pilot Projects Program
试点项目计划
  • 批准号:
    10630581
  • 财政年份:
    2023
  • 资助金额:
    $ 49.72万
  • 项目类别:
Integrative Role of Bilirubin on Obesity
胆红素对肥胖的综合作用
  • 批准号:
    10555196
  • 财政年份:
    2020
  • 资助金额:
    $ 49.72万
  • 项目类别:
The Renal Medulla and Hypertension
肾髓质和高血压
  • 批准号:
    7838856
  • 财政年份:
    2009
  • 资助金额:
    $ 49.72万
  • 项目类别:
The Renal Medulla and Hypertension
肾髓质和高血压
  • 批准号:
    7525451
  • 财政年份:
    2008
  • 资助金额:
    $ 49.72万
  • 项目类别:
The Renal Medulla and Hypertension
肾髓质和高血压
  • 批准号:
    7673973
  • 财政年份:
    2008
  • 资助金额:
    $ 49.72万
  • 项目类别:
The Renal Medulla and Hypertension
肾髓质和高血压
  • 批准号:
    7918042
  • 财政年份:
    2008
  • 资助金额:
    $ 49.72万
  • 项目类别:
The Renal Medulla and Hypertension
肾髓质和高血压
  • 批准号:
    8316332
  • 财政年份:
    2008
  • 资助金额:
    $ 49.72万
  • 项目类别:
INTRARENAL RAS AND BLOOD PRESSURE REGULATION
肾内 RAS 和血压调节
  • 批准号:
    2910494
  • 财政年份:
    1999
  • 资助金额:
    $ 49.72万
  • 项目类别:
INTRARENAL RAS AND BLOOD PRESSURE REGULATION
肾内 RAS 和血压调节
  • 批准号:
    2520575
  • 财政年份:
    1998
  • 资助金额:
    $ 49.72万
  • 项目类别:
Project 1 - Role of Bilirubin in Protection against Cardiometabolic Syndrome in Obesity
项目 1 - 胆红素在预防肥胖症心脏代谢综合征中的作用
  • 批准号:
    9573136
  • 财政年份:
  • 资助金额:
    $ 49.72万
  • 项目类别:

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