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：
DAVID E STEC
金额：
$ 49.72万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
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

来源：
https://reporter.nih.gov/project-details/10337279
关键词：
20 year old Address Animals Anti-Inflammatory Agents Antidiabetic Drugs Antioxidants Attenuated Bile Pigments Bilirubin Biliverdin reductase Biliverdine Body mass index Cardiovascular Diseases Cells Chronic Correlative Study Data Development Diabetes Mellitus Disease Disease Resistance Enzymes Family Fasting Fatty Liver Gene Activation Generations Genes Genetic Transcription Glycogen Synthase Kinases Goals Hepatic Hepatocyte Hyperbilirubinemia Hyperglycemia Incidence Insulin Resistance Knock-out Knowledge Lipids Liver Mediating Metabolic syndrome Modeling Molecular Morbidity - disease rate Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Receptors Obesity Outcome Overweight PPAR alpha Pathway interactions Peroxisome Proliferator-Activated Receptors Persons Physiology Plasma Population Study Prevention therapy Property Protein Kinase Public Health Receptor Activation Receptor Signaling Research Role Serum Signal Transduction Signaling Molecule Techniques Testing Time UGT1A1 enzyme UGT1A1 gene antagonist blood pressure reduction cardiovascular risk factor chronic liver disease diabetic dietary fibroblast growth factor 21 mortality new therapeutic target non-alcoholic fatty liver disease novel novel therapeutics obese person obesity treatment oxidation public health relevance receptor function response transcription factor treatment strategy

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 导致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。