Integrative Role of Bilirubin on Obesity

胆红素对肥胖的综合作用

基本信息

  • 批准号:
    10555196
  • 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 2025-01-31
  • 项目状态:
    未结题

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.
抽象的 肥胖是非酒精性脂肪肝病 (NAFLD) 和 II 型糖尿病的主要原因。这两个 这些条件导致肥胖的发病率和死亡率。大量人口研究已 证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首次证明胆红素也是一种信号传导 能够通过核激素受体(例如过氧化物酶体增殖物激活受体(PPARα))发出信号的分子 此外,胆红素还可以灭活糖原合成酶激酶 3Beta(GSK3Beta) 增加 PPARα 靶基因,如成纤维细胞生长因子 21 (FGF21);但具体作用 GSK3Beta 失活/PPARα 激活对中度抗脂肪变性和抗糖尿病作用 高胆红素血症尚不清楚。胆绿素还原酶 (BVR) 是负责还原胆绿素的酶。 胆绿素转化为胆红素。它可以产生血浆​​中的胆红素以及体内产生的胆红素 细胞。该提案的目的是检验胆红素和 BVRA 可以预防的中心假设 肥胖通过激活 PPARα 信号轴诱导肝脂肪变性和胰岛素抵抗。目标 1 的 该提案将检验以下假设:胆红素治疗导致慢性中度高胆红素血症 或拮抗肝脏UGT1A1可逆转饮食肥胖引起的肝脂肪变性和肝胰岛素 反抗。该提案的目标 2 将检验中度高胆红素血症逆转肝功能的假设 通过激活 PPARα 来实现脂肪变性和胰岛素抵抗。该提案的目标 3 将检验以下假设: 肝胆红素生成的特定损失通过以下方式增强肝脂肪变性和胰岛素抵抗: GSK3Beta 介导的途径可降低 PPARα 活性。提案中概述的研究结果将 对中度高胆红素血症作为一种新疗法的发展具有深远的影响 治疗肥胖引起的 NAFLD 和胰岛素抵抗。这些研究还将确定新的作用 胆红素作为核激素受体信号分子及其在保护中的作用 对抗肥胖引起的 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:
    10337279
  • 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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