Novel Liver Signaling Pathways Controlling Adiposity

控制肥胖的新型肝脏信号通路

基本信息

批准号：
10376254
负责人：
Terry D Hinds
金额：
$ 41.01万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2020-07-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376254
关键词：
Adenovirus Vector Adipocytes Adipose tissue Adult Affect Antioxidants Attenuated Bile fluid Bilirubin Biliverdin reductase Biliverdine Binding Blood Blood Glucose Body Weight Body Weight decreased Cardiovascular Diseases Cardiovascular system Categories Cell Size Crigler-Najjar Syndrome Data Deposition Diabetes Mellitus Energy Intake Energy Metabolism Enzymes Event Excretory function Expenditure Fatty Liver Fatty acid glycerol esters Fenofibrate Genes Genetic Genetic Polymorphism Gilbert Disease Glucose Glucose Intolerance Health Hepatic Hepatocyte Hepatotoxicity High Fat Diet Hormones Human Hyperbilirubinemia Icterus Inflammatory Inherited Insulin Insulin Resistance Intestines Investigation Knock-out Knockout Mice Knowledge Lead Ligands Lipids Liver Liver diseases LoxP-flanked allele Measures Mediating Medical Metabolic Metabolic hormone Metabolism MicroRNAs Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obese Mice Obesity Obesity Epidemic Obesity associated disease Outcome Overweight Oxidative Stress PPAR alpha Pathologic Pathway interactions Patients Peripheral Peroxisome Proliferator-Activated Receptors Physiological Plasma Population Study Process Protein Isoforms Publications Resistance Risk Rodent Serum Signal Pathway Signal Transduction Signaling Molecule Testing Therapeutic Tissues Transactivation UDP-Glucuronosyltransferase 1A1 Uncertainty United States Visceral fat Weight Gain carbohydrate metabolism clinically relevant cost cytokine fatty liver disease fibroblast growth factor 21 hormonal signals humanized mouse improved insulin sensitivity lipid metabolism mouse model non-alcoholic fatty liver disease novel novel therapeutics obese patients oxidation preference promoter recruit transcription factor

项目摘要

There is little doubt that we are in the midst of a worldwide epidemic of obesity. Almost two-thirds of adults in the United States are obese or overweight. Whether if obesity arises from genetic factors or high caloric intake, it still may lead to insulin resistance and type II diabetes. Our recent data show that bilirubin (BR), which has been typically considered as an antioxidant, may function as a metabolic ligand that signals to the nuclear receptor transcription factor PPARα to reduce lipid accumulation. We also found that BR induces the hepatic fibroblast growth factor 21 (FGF21) hormone via PPARα, which is known to have systemic effects on insulin sensitivity. Hepatic lipid accumulation and insulin resistance are interlocking pathophysiologic events, but the mechanisms of these abnormalities, and how these distinct processes interact, are inadequately understood. For unknown reasons, BR plasma levels are lower in the obese, and several obese patients progress to nonalcoholic fatty liver disease (NAFLD), which is likely due to obesity-induced insulin resistance. However, in patients with pathological liver disease such as Crigler-Najjar syndrome, the BR plasma levels are very high. This paradox may be explained by the hepatic UDP-glucuronosyltransferase 1-1 (UGT1A1) enzyme that conjugates BR to make it soluble and for deposition into bile and eventually into the intestine, which lowers unconjugated BR from the blood. In humans, a polymorphism in the UGT1A1 gene (UGT1A1*28), known as Gilbert’s syndrome (GS), reduces expression resulting in increased plasma BR levels but not in liver disease. We have shown that humanized mice with the Gilbert’s polymorphism (UGT1A1*28) on a high-fat diet have significantly higher plasma BR levels, reduced adiposity and insulin intolerance, and are resistant to fatty liver disease. Agents that regulate Ugt1a1 during weight gain or loss are unknown. In the preliminary data, we show exciting data that microRNA- 365 (miR365) suppresses Ugt1a1 expression and increases plasma BR levels. We also found that Ugt1a1 expression is higher in the livers of obese mice, while miR365 and plasma BR levels are lower, which indicates that miR365 targeting Ugt1a1 may be beneficial in increasing plasma BR to regulate adiposity. Our central hypothesis is that BR functions as a metabolic ligand that activates the liver PPARα-FGF21 pathway to reduce adiposity and insulin resistance. We will pursue this plan with three primary scientific aims: 1) Determine the selectivity of BR on PPAR isoforms; 2) Determine the systemic effects of BR mediated by hepatic FGF21; and, 3) Determine if miR365 elevation of BR reduces adiposity and insulin resistance via PPARα. Collectively, this project is the first systematic investigation of the BR-PPARα-FGF21 module and its control of insulin resistance associated with obesity. The proposal provides advances to new strategies (miR365) of targeting this module to control adiposity which offers therapeutic benefits.

毫无疑问，我们正处于全球范围内肥胖流行的时期，近三分之二的成年人患有肥胖症。美国人肥胖或超重，无论肥胖是源于遗传因素还是高热量摄入。我们最近的数据显示，胆红素（BR）仍然可能导致胰岛素抵抗和II型糖尿病。通常被认为是一种抗氧化剂，可以作为向核受体发出信号的代谢配体我们还发现 BR 可以诱导肝成纤维细胞形成。通过 PPARα 产生生长因子 21 (FGF21) 激素，已知 PPARα 对胰岛素敏感性具有全身性影响。肝脏脂质蓄积和胰岛素抵抗是相互关联的病理生理事件，但其机制这些异常的原因以及这些不同过程如何相互作用尚不清楚。原因是，肥胖者的 BR 血浆水平较低，并且一些肥胖患者进展为非酒精性脂肪肝肝脏疾病（NAFLD），这可能是由于肥胖引起的胰岛素抵抗。病理性肝病如Crigler-Najjar综合征时，BR血浆水平非常高，这一悖论。可能是通过肝 UDP-葡萄糖醛酸基转移酶 1-1 (UGT1A1) 酶将 BR 缀合来解释的使其可溶并沉积到胆汁中并最终进入肠道，从而降低未结合的 BR 在人类血液中，UGT1A1 基因 (UGT1A1*28) 存在多态性，称为吉尔伯特综合征 (GS)，表达降低会导致血浆 BR 水平升高，但不会导致肝脏疾病。具有吉尔伯特多态性 (UGT1A1*28) 的人源化小鼠在高脂肪饮食下具有显着更高的血浆 BR 水平，减少肥胖和胰岛素不耐受，并抵抗脂肪肝疾病的调节剂。体重增加或减少期间的 Ugt1a1 未知。在初步数据中，我们显示了令人兴奋的数据，即 microRNA-。 365 (miR365) 抑制 Ugt1a1 表达并增加血浆 BR 水平。肥胖小鼠肝脏中表达较高，而 miR365 和血浆 BR 水平较低，这表明靶向 Ugt1a1 的 miR365 可能有益于增加血浆 BR 来调节肥胖。假设 BR 作为代谢配体，激活肝脏 PPARα-FGF21 途径，以减少我们将通过三个主要科学目标来实施该计划：1) 确定肥胖和胰岛素抵抗。 BR 对 PPAR 同工型的选择性；2) 确定 BR 由肝 FGF21 介导的全身效应； 3) 确定 BR 的 miR365 升高是否通过 PPARα 减少肥胖和胰岛素抵抗。该项目是第一个针对 BR-PPARα-FGF21 模块及其对胰岛素抵抗的控制的系统研究该提案为针对该模块的新策略（miR365）提供了进展。控制肥胖，提供治疗益处。