Novel Liver Signaling Pathways Controlling Adiposity

控制肥胖的新型肝脏信号通路

• 批准号: 10210389
• 负责人: Terry D Hinds
• 金额: $ 40.84万
• 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/10210389
• 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; 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，我们正处于全球肥胖症的流行之中。世界上近三分之二的成年人 美国人肥胖或超重。无论肥胖是由遗传因素还是高卡路里摄入量引起的 仍然可能导致胰岛素抵抗和II型糖尿病。我们最近的数据显示，胆红素(BR)一直是 通常被认为是一种抗氧化剂，可能作为代谢配体向核受体发出信号 转录因子PPARα可减少脂肪堆积。我们还发现BR可以诱导肝成纤维细胞 生长因子21(FGF21)激素通过PPARα，已知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，以及这些不同的过程是如何相互作用的，都没有得到充分的了解。对于未知 原因是，肥胖者血浆BR水平较低，几名肥胖者进展为非酒精性脂肪 肝脏疾病(NAFLD)，这可能是由于肥胖导致的胰岛素抵抗。然而，在患有 病理性肝病如Crigler-Najjar综合征，血浆BR水平非常高。这一悖论 可能由肝脏UDP-葡萄糖醛酸基转移酶1-1(UGT1A1)酶解释，UGT1A1酶将BR与 使其溶解，并沉积到胆汁中，最终进入肠道，从而降低未结合的BR 鲜血。在人类中，UGT1A1基因(UGT1A1*28)的多态被称为吉尔伯特综合征(GS)， 减少表达会导致血浆BR水平升高，但在肝病中不会。我们已经证明了 在高脂饮食中具有Gilbert‘s多态(UGT1A1*28)的人源化小鼠的血浆水平显著升高 BR水平，减少肥胖和胰岛素耐受，并对脂肪肝疾病具有抵抗力。监管机构 体重增加或减少期间的UGT1A1尚不清楚。在初步数据中，我们展示了令人兴奋的数据，即microRNA- 365(MiR365)抑制UGT1A1的表达并增加血浆BR水平。我们还发现UGT1A1 肥胖小鼠肝脏中的表达较高，而miR365和血浆BR水平较低，这表明 靶向UGT1A1的miR365可能有助于增加血浆BR以调节肥胖。我们的中央 假说认为，BR作为代谢配体激活肝脏PPARα-FGF21途径，使其减少 肥胖和胰岛素抵抗。我们将带着三个主要的科学目标来追求这一计划：1)确定 BR对PPAR亚型的选择性；2)决定由肝脏FGF21介导的BR的全身效应；以及， 3)确定miR365BR的升高是否通过PPARα降低肥胖和胰岛素抵抗。总而言之，这 该项目是首次系统研究BR-PPARα-FGF21模块及其对胰岛素抵抗的控制 与肥胖有关。该提案提供了针对此模块的新战略(MiR365)的进展 控制肥胖，这提供了治疗的好处。