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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，我们正处于世界范围的肥胖流行之中。近三分之二的成年人在美国人肥胖或超重。无论肥胖是由遗传因素还是高热量摄入引起，仍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），这一直是通常被认为是一种抗氧化剂，可以作为一种代谢配体，向核受体发出信号转录因子过氧化物酶体增殖物激活受体α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（FGF 21）激素通过PPARα，这是已知的对胰岛素敏感性的全身性影响。肝脏脂质积聚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，以及这些不同的过程如何相互作用，还没有得到充分的理解。因不明由于这些原因，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。然而，在患有病理性肝病如Crigler-Najjar综合征，BR血浆水平非常高。这一悖论可以通过肝UDP-葡萄糖醛酸基转移酶1-1（UGT 1A 1）酶来解释，该酶将BR结合到使其可溶并沉积到胆汁中，最终进入肠道，这降低了未结合的BR，血在人类中，UGT 1A 1基因（UGT 1A 1 *28）的多态性，称为吉尔伯特综合征（GS），降低表达，导致血浆BR水平增加，但不导致肝脏疾病。我们已经证明具有吉尔伯特多态性（UGT 1A 1 *28）的高脂饮食的人源化小鼠具有显著更高的血浆 BR水平，减少肥胖和胰岛素不耐受，并抵抗脂肪肝疾病。调节剂 Ugt 1a 1在体重增加或减轻期间是未知的。在初步数据中，我们展示了令人兴奋的数据，即microRNA- 365（miR 365）抑制Ugt 1a 1表达并增加血浆BR水平。我们还发现Ugt 1a 1 肥胖小鼠肝脏中miR 365的表达较高，而miR 365和血浆BR水平较低，这表明靶向Ugt 1a 1的miR 365可能有利于增加血浆BR以调节肥胖。我们的中央假设BR作为代谢配体发挥作用，激活肝脏PPARα-FGF 21途径，肥胖和胰岛素抵抗。我们将以三个主要的科学目标来执行这个计划：1）确定 BR对PPAR亚型的选择性; 2）确定由肝FGF 21介导的BR的全身作用;和， 3)确定BR的miR 365升高是否通过PPARα降低肥胖和胰岛素抵抗。总的来说，这该项目是首次系统研究BR-PPARα-FGF 21模块及其对胰岛素抵抗的控制与肥胖有关。该提案提供了针对该模块的新策略（miR 365）的进展，控制肥胖，这提供了治疗益处。

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.