CLOCK Regulation of Liver Metabolism via Modulation of HNF-4alpha

通过 HNF-4alpha 调节肝脏代谢的时钟调节

基本信息

批准号：
7807318
负责人：
Kristin Eckel Mahan
金额：
$ 4.76万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7807318
关键词：
Acetylation Acetyltransferase Address Adipose tissue Affect Animals Anterior Hypothalamus BHLH Protein Bacteria Bile Acids Binding Biochemistry Biological Rhythm Body Temperature Body Weight Boxing Brain Catabolism Cell Line Cell Nucleus Cell physiology Cells Cholesterol Chromatin Circadian Rhythms Clock protein Complex Crying Cues Defect Electronic Mail Embryo Environment Enzymes Epigenetic Process Event Eye Feedback Fibroblasts Future Gene Targeting Genes Genetic Polymorphism Genetic Transcription Gluconeogenesis Glucose Goals Hepatic Hepatocyte Heterodimerization Histone Acetylation Histone Deacetylase Histone H3 Histones Homeostasis Homologous Gene Hormones Hour Human In Vitro Individual Intestines Kidney Knock-out Knockout Mice Lead Light Link Lipids Liver Lysine Maintenance Mating Types Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Modification Molecular Molecular Biology Mus Mutate Mutation Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Obesity Organism Outcome Pacemakers Pancreas Peripheral Phenotype Physiological Processes Physiology Protein Acetylation Proteins Regulation Retinal Ganglion Cells Rodent Role Sleep Sleep Wake Cycle Stomach Structure of beta Cell of islet System Time Tissues Transcription Coactivator adenoviral-mediated blood glucose regulation circadian pacemaker cryptochrome early onset feeding food restriction glucose metabolism histone acetyltransferase human HNF4A protein in vivo insight knockout animal lipid metabolism liver metabolism member mutant promoter receptor expression research study suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): The goals set forth in this proposal address the role of the endogenous circadian clock in the regulation of metabolism, specifically, glucose and lipid homeostasis. Circadian rhythms are endogenously generated oscillations that take place in the course of a day. Environmental cues (zeitgebers) such as light and dark assist in the synchronization and maintenance of endogenous circadian rhythms, however, circadian rhythms are intrinsic, controlled at the cellular level by complex transcriptional feedback regulation by circadian clock genes including Clock, Bmall, Period and Cryptochrome. While the circadian system is in control of biological rhythms such as the sleep-wake cycle, hormone secretion, and body temperature, evidence is accumulating that there is a direct link between circadian rhythm and metabolism. Numerous transcriptional activators essential for metabolism (including the members of the nuclear receptor superfamily) appear to undergo circadian oscillations in metabolically active tissues. Furthennore, dismptions in circadian clock genes result in aberrations in lipid and glucose homeostasis as well as obesity. CLOCK, best known for its role as a circadian-regulating transcriptional activator, was recently discovered to have acetyltransferase activity, functioning as an enzyme to posttranslationally modify target proteins. The proposal set forth gives preliminary evidence that CLOCK binds to and posttranslationally modifies HNF-4a, a protein central to gluconeogenesis and cholesterol catabolism into bile acids. The central hypothesis of this proposal is that the binding of HNF-4a and its subsequent modification by circadian machinery is critical for nomnal glucose homeostasis. HNF-4a is essential for nomnal lipid and glucose metabolism as well as for normal pancreatic beta cell function. In fact, mutations in HNF-4a cause the early onset of type II diabetes, commonly referred to as maturity-onset diabetes of the young (MODY). Alterations in circadian rhythm produce profound disturbances in lipid and glucose homeostasis as well as body weight regulation. This phenotype begs the question of how exactly they function in metabolically active tissues. This proposal demonstrates ways in which CLOCK protein might impinge on metabolism in a manner which has not yet been considered, through direct interaction with and modification of HNF-4a. We would like to detemiine how the circadian system affects HNF-4a in the liver in order to understand why circadian disturbances can produce such profound changes in lipid metabolism and body weight regulation. This study may provide insight into how circadian clock machinery might be used in the future as a target for the conection or manipulation of glucose homeostasis in the body

描述（由申请人提供）：该提案中提出的目标涉及内源性昼夜节律在代谢调节中的作用，特别是葡萄糖和脂质稳态。昼夜节律是在一天中发生的内源性产生的振荡。但是，环境提示（Zeitgeber），例如光和黑暗的辅助和维持内源性昼夜节律的同步和维持，昼夜节律是固有的，通过复杂的转录反馈调节在细胞水平上通过昼夜节律钟表控制在细胞水平上受控，包括时钟，bmall，bmall，ofiper，ofience and ofence and ofence and Crypiclome。虽然昼夜节律系统控制着生物节奏，例如睡眠效果周期，激素分泌和体温，但有证据表明昼夜节律与代谢之间存在直接联系。代谢所必需的许多转录激活剂（包括核受体超家族的成员）似乎在代谢活性组织中经历了昼夜振荡。此外，昼夜节律基因的沮丧导致脂质和葡萄糖稳态和肥胖。最近发现以其作为昼夜节律转录激活剂的作用而闻名的时钟，最近被发现具有乙酰转移酶活性，可作为翻译后修饰靶蛋白的酶作用。提出的提案提供了初步证据，表明时钟与翻译后的结合并修饰了HNF-4A，这是糖异生和胆固醇分解代谢与胆汁酸的中心的蛋白质。该提议的中心假设是HNF-4A的结合及其随后通过昼夜节律的修饰对于Nomnal葡萄糖稳态至关重要。 HNF-4A对于NOMNal脂质和葡萄糖代谢以及正常的胰腺β细胞功能至关重要。实际上，HNF-4A中的突变会引起II型糖尿病的早期发作，通常称为年轻人（Mody）的成熟度 - 发作性糖尿病。昼夜节律的改变会在脂质和葡萄糖稳态以及体重调节中产生深刻的干扰。该表型引出了一个问题，即它们在代谢活性组织中的确切作用。该提案展示了通过与HNF-4A的直接相互作用和修改，以尚未考虑的方式可能会以尚未考虑的方式对新陈代谢构成新陈代谢的方式。我们想逐渐消除昼夜节律系统如何影响肝脏中的HNF-4A，以了解为什么昼夜节律障碍会在脂质代谢和体重调节中产生如此深刻的变化。这项研究可能会提供有关将来如何将昼夜节律机械用作对体内葡萄糖稳态进行反应或操纵的目标的洞察力