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：
10596569
负责人：
Terry D Hinds
金额：
$ 41.37万
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/10596569
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 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 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 Shapes Signal Pathway Signal Transduction Signaling Molecule Testing Therapeutic Tissue Expansion Tissues Transactivation UDP-Glucuronosyltransferase 1A1 Uncertainty United States Visceral fat Weight Gain carbohydrate metabolism clinically relevant comparison control cost cytokine fatty liver disease fibroblast growth factor 21 hormonal signals humanized mouse improved insulin sensitivity lipid metabolism microRNA delivery 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，我们正处于肥胖症的全球流行病中。几乎三分之二的成年人美国是肥胖或超重。如果肥胖是遗传因素还是高热量摄入，则仍然可能导致胰岛素抵抗和II型糖尿病。我们最近的数据表明，胆红素（BR）已经通常被认为是抗氧化剂，可能是向核接收器发出信号的代谢配体转录因子PPARα减少脂质积累。我们还发现BR诱导肝成纤维细胞生长因子21（FGF21）激素通过PPARα，该激素对胰岛素敏感性具有全身影响。肝脂质积累和胰岛素抵抗是互锁的病理生理事件，但是机制这些异常以及这些不同的过程如何相互作用是不充分理解的。对于未知原因，肥胖的BR血浆水平较低，几名肥胖患者发展为非酒精性脂肪肝病（NAFLD），这可能是由于肥胖引起的胰岛素抵抗。但是，在患者中病理肝病，例如Crigler-Najjar综合征，BR血浆水平很高。这个悖论可以用肝UDP-葡萄糖基转移酶1-1（ugt1a1）酶来解释，该酶将BR结合到使其可溶并沉积到胆汁中，并最终进入肠子，从而降低了未结合的BR 鲜血。在人类中，UGT1A1基因（UGT1A1*28）中的多态性，称为吉尔伯特综合症（GS），降低表达，导致血浆BR水平升高，但在肝病中没有升高。我们已经表明具有吉尔伯特多态性（UGT1A1*28）的人源化小鼠在高脂饮食上具有更高的血浆 BR水平，脂肪降低和胰岛素耐药性，对脂肪肝病有抵抗力。调节的代理体重增加或损失期间的UGT1A1尚不清楚。在初步数据中，我们显示了令人兴奋的数据，这些数据是microRNA- 365（miR365）抑制了UGT1A1表达并增加了血浆BR水平。我们还发现UGT1A1 肥胖小鼠的生活中的表达较高，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以调节肥胖。我们的中心假设是BR充当一种代谢配体，可激活肝脏PPARα-FGF21途径以减少肥胖和胰岛素抵抗。我们将以三个主要的科学目的来实现这一计划：1）确定 BR对PPAR同工型的选择性； 2）确定由肝FGF21介导的BR的全身效应；和， 3）确定MIR365 BR的升高是否会通过PPARα降低肥胖和胰岛素抵抗。总的来说，这项目是BR-PPARα-FGF21模块的首次系统投资及其对胰岛素抵抗的控制与肥胖有关。该提案为针对该模块的新策略（MIR365）提供了进步控制肥胖，提供治疗益处。