权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10763473
负责人：
Terry D Hinds
金额：
$ 6.9万
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/10763473
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。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FKBP51 and the molecular chaperoning of metabolism.

DOI：
10.1016/j.tem.2021.08.003
发表时间：
2021-11
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
0
作者：
Smedlund KB;Sanchez ER;Hinds TD Jr
通讯作者：
Hinds TD Jr

Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.

糖皮质激素、其用途、性别二态性和疾病：新概念、机制和发现。

DOI：
10.1152/physrev.00021.2023
发表时间：
2024
期刊：
Physiological reviews
影响因子：
33.6
作者：
Martinez,GeneseeJ;Appleton,Malik;Kipp,ZacharyA;Loria,AnaliaS;Min,Booki;HindsJr,TerryD
通讯作者：
HindsJr,TerryD

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways.