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

• 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
• 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

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)： 这项提案中提出的目标涉及内源性生物钟在新陈代谢调节中的作用，特别是葡萄糖和脂肪的稳态。昼夜节律是一天中发生的内源性振荡。环境线索(如光和暗)有助于内源性昼夜节律的同步和维持，然而，昼夜节律是内在的，在细胞水平上受复杂的转录反馈调控，由时钟、Bmall、周期和隐色素等生物钟基因控制。虽然昼夜节律系统控制着生物节律，如睡眠-觉醒周期、激素分泌和体温，但越来越多的证据表明，昼夜节律和新陈代谢之间存在直接联系。许多对新陈代谢至关重要的转录激活物(包括核受体超家族的成员)似乎在代谢活跃的组织中经历昼夜振荡。此外，生物钟基因的缺失会导致脂质和蛋白质的异常 葡萄糖动态平衡和肥胖。Clock以其调节昼夜节律的转录激活剂的作用而闻名，最近被发现具有乙酰转移酶的活性，作为一种酶在翻译后修饰靶蛋白。该提案提供了初步证据，证明Clock结合并在翻译后修饰HNF-4a，HNF-4a是一种对糖异生和胆固醇分解代谢为胆汁酸至关重要的蛋白质。 这一建议的中心假设是，HNF-4a的结合及其随后的昼夜机制的修饰对于正常的葡萄糖稳态是至关重要的。HNF-4a对正常的脂肪和葡萄糖代谢以及正常的胰岛β细胞功能是必不可少的。事实上，HNF-4a的突变会导致II型糖尿病的早期发病，通常被称为青年成熟型糖尿病(MODY)。昼夜节律的改变会严重扰乱血脂和血糖的动态平衡以及体重调节。 这种表型回避了它们在新陈代谢活跃的组织中究竟如何发挥作用的问题。这一提议展示了时钟蛋白可能通过与HNF-4a的直接相互作用和修饰而以一种尚未被考虑的方式影响新陈代谢的方式。我们想要检测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紊乱会在脂肪代谢和体重调节方面产生如此深刻的变化。这项研究可能为将来如何利用生物钟机制作为连接或操纵体内葡萄糖稳态的靶标提供洞察力。