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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.

摘要