Novel Liver Signaling Pathways Controlling Adiposity

控制肥胖的新型肝脏信号通路

• 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
• 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

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世界性流行之中。几乎三分之二的成年人