Mechanisms of high fat diet-induced circadian hepatic transcription and lipid metabolism reprogramming

高脂饮食诱导昼夜节律肝转录和脂质代谢重编程的机制

• 批准号: 9896819
• 负责人: Dongyin Guan
• 金额: $ 2.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896819
• 关键词: Address; Architecture; Biochemical Genetics; Bioinformatics; Cardiovascular Diseases; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Complement; Complex; Data; Diabetes Mellitus; Diet; Elements; Enhancers; Environment; Equilibrium; Feedback; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hepatic; Hepatocyte; High Fat Diet; Hypertension; Individual; Institution; Knock-out; Knockout Mice; Laboratories; Light; Lipids; Liver; Malignant Neoplasms; Maps; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Modernization; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; PPAR alpha; Pathway interactions; Pennsylvania; Periodicity; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Physiology; Preparation; Prevalence; Proteins; Regulator Genes; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Signal Transduction; Site; Sleep Disorders; Societies; Techniques; Therapeutic; Training; Universities; Up-Regulation; career; circadian; circadian pacemaker; collaborative environment; epidemiology study; epigenomics; estrogen-related receptor; fatty acid oxidation; feeding; functional genomics; genetic information; genome-wide; global run on sequencing; in vivo; innovation; insight; lipid biosynthesis; lipid metabolism; loss of function; mouse model; obesity risk; receptor; receptor binding; shift work

Project Summary Epidemiological studies have demonstrated people who suffer from overnutrition are prone to developing metabolic diseases such as type-2 diabetes, cardiovascular disease, hypertension and cancer. In modern society, circadian misalignment is increasingly recognized as a risk factor for metabolic disorders. For example, night shift workers and individuals with sleep disorders are at an increased risk of developing obesity, diabetes, and related metabolic diseases, similar to the result of overnutrition. However, how the nutritive environment impacts on global transcriptional and epigenomic circadian rhythms is not well understood. The goal of this proposal is to understand the mechanisms by which hypernutrition induces reprogramming of circadian transcription, and to evaluate the effects of key regulators on lipid metabolism under these pathophysiological conditions. My preliminary data have demonstrated global transcriptional remodeling in mouse livers after a hypernutritive, high-fat diet (HFD) challenge. Specific Aim 1 is to dissect the molecular mechanism of HFD-induced enhancer remodeling and rhythmic transcription reprogramming. A genetic loss-of-function approach using PPARα and ERR γ knockout mouse models and state-of-the-art genome-wide approaches will be applied to unbiasedly characterize the regulatory roles of PPARα and ERRγ under overnutrition conditions. Specific Aim 2 is to determine the physiological consequences of HFD-induced rhythmic de novo lipogenesis (DNL) and fatty acid oxidation (FAO) pathways in overall hepatic lipid metabolism. We have determined the rhythmicity of FAO rate is consistent with the rhythmic expression of genes involved in FAO. In this aim, I will determine the de novo lipogenesis rate in vivo to parse out the physiological effects of HFD-enhanced rhythmicity of DNL. Moreover, to determine the putative interactions of DNL and FAO, the induction of SREBP and PPARα in same or different hepatocytes will be examined and the effect of SCAP (master regulator of DNL) knockout on the circadian rhythm of FAO in HFD-fed mice will be further determined. Through the innovative and comprehensive research strategy detailed in this proposal, the applicant, Dr. Dongyin Guan, will gain extensive training in bioinformatics and metabolic physiology techniques, which are vital to a career in metabolic and circadian rhythm research at a top academic institution. The proposed site of research, University of Pennsylvania, is a state-of-the-art institution, providing the technologically advanced resources necessary to carry out the proposed research. The sponsor, Dr. Mitchell A. Lazar, is a world- renowned gene transcription and metabolism researcher, who will provide the ideal collaborative environment to train Dr. Guan in preparation for a career in metabolism research. The research proposed here will serve to address the relevance of the counterintuitive and concordant up-regulation of lipid anabolic and catabolic pathways under HFD and may uncover the molecular underpinnings of hepatic lipid dysregulation associated with hypernutritive feeding.

项目摘要 流行病学研究表明，患有营养的人容易发展 代谢性疾病，例如2型糖尿病，心血管疾病，高血压和癌症 社会，昼夜节律越来越多地被认为是代谢疾病的危险因素。 夜班工人和患有睡眠障碍的人会出现肥胖，糖尿病，糖尿病的风险。 和相关的代谢性疾病，类似于过度营养不良的结果。 对全球转录和表观基因组苏打节律的影响没有。 提案是要了解满足性诱导昼夜节律重新编程的机制 转录，并评估关键常规者对脂质代谢的影响 条件。 高脂饮食（HFD）挑战1。 HFD诱导的增强子的重塑和节奏转录重编程 使用PPARα和ERRγ基因型小鼠小鼠模型和最先进基因组的方法的方法将会 被应用于育儿下PPARα和错误的常规作用。 具体目标2是确定HFD诱导的节奏的生理后果 整体肝脂质代谢中的脂肪生成（DNL）和脂肪酸氧化（FAO）途径 已经确定了粮农组织率的节奏与涉及的基因的节奏表达一致 粮农组织。 HFD增强的节奏性，以确定DNL和FAO的推定相互作用 将检查SREBP和PPARα在相同或不同的肝细胞中的行业和SCAP的影响 （DNL的主调节器）将进一步确定HFD喂养小鼠中粮农组织昼夜节律的淘汰。 通过本提案中详细介绍的创新和全面的研究策略，申请人博士 Dongyin Guan将获得广泛的生物信息学和代谢生理学技术的培训，这是 在顶级学术机构中，对代谢和昼夜节律研究的职业至关重要。 研究，宾夕法尼亚大学，是一种最先进的进攻 进行支撑研究所需的资源。 著名的基因转录和代谢研究人员，他们将提供理想的碰撞环境 培训博士为代谢研究做准备。 解决脂质和分解代谢的违反直觉和一致上调的相关性 HFD下的途径可能会发现肝脂质功能障碍相关的分子基础 摄取生育喂养。