Integrative Role of Bilirubin on Obesity

胆红素对肥胖的综合作用

• 批准号: 10555196
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10555196
• 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; Research; Role; Serum; Signal Transduction; Signaling Molecule; Techniques; Testing; Time; UGT1A1 enzyme; UGT1A1 gene; antagonist; blood pressure reduction; cardiovascular risk factor; chronic liver disease; dietary; fibroblast growth factor 21; mortality; new therapeutic target; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; novel therapeutics; obese person; obesity treatment; oxidation; public health relevance; response; transcription factor

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 条件有助于肥胖的发病率和死亡率。大量人口研究 表现出血清胆红素水平与NAFLD和II型的发展之间的负相关性 糖尿病。尽管进行了这些相关研究，但胆红素可以保护NAFLD和类型的机制 II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信号传导 能够通过核激素受体发出信号的分子，例如过氧化物酶体增生剂激活受体（PPARALPHA），此外，胆红素还可以使糖原合酶激酶激酶-3beta（GSK3BETA）do胆红素还可以灭活 增加pParalpha靶基因，例如成纤维细胞生长因子21（FGF21）；但是， GSK3BETA失活/pParalpha激活中度的抗溶裂性和抗糖尿病作用 高胆红素血症尚不清楚。 Biliverdin还原酶（BVR）是负责还原的酶 biliverdin到胆红素。它可以产生在血浆中发现的胆红素以及内部产生的胆红素 细胞。该提议的目的是检验胆红素和BVRA防止的中心假设 肥胖症通过激活pParalpha信号轴诱导肝脂肪变性和胰岛素抵抗。目标1 该提案将检验以下假设：胆红素治疗引起的慢性中度高胆红素血症 或肝UGT1A1的拮抗作用可以逆转饮食肥胖症诱发肝脂肪变性和肝胰岛素 反抗。该提案的目标2将检验中等高胆红素血症逆转肝的假设 脂肪变性和胰岛素耐药性通过pParalpha激活。该提案的目标3将检验以下假设。 肝胆红素产生的特定损失可通过A增强肝脂肪变性和胰岛素抵抗 GSK3BETA介导的途径降低了pParalpha活性。提案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影响，作为一种新的疗法 肥胖诱导的NAFLD和胰岛素抵抗的治疗。这些研究还将决定 胆红素作为核激素受体信号分子，该机制在保护中的作用 反对肥胖引起的NAFLD和胰岛素抵抗。