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，营养过剩的人容易患上 代谢性疾病，如2型糖尿病、心血管疾病、高血压和癌症。在现代 在社会上，昼夜节律失调越来越被认为是代谢紊乱的危险因素。例如, 夜班工人和有睡眠障碍的人患肥胖症、糖尿病、 以及相关的代谢性疾病，类似于营养过剩的结果。然而，营养丰富的环境 对全球转录和表观基因组昼夜节律的影响还不是很清楚。这样做的目的是 建议理解高营养导致昼夜节律重新编程的机制。 转录，并评估在这些病理生理条件下关键调节剂对脂代谢的影响 条件。我的初步数据显示，在小鼠肝脏中， 高营养、高脂肪饮食(HFD)挑战。具体目标1是剖析黄曲霉毒素的分子机制 HFD诱导的增强子重塑和节律性转录重编程。遗传性功能丧失 使用PPARα和ERRγ基因敲除小鼠模型的方法和最先进的全基因组方法将 被用来无偏见地表征营养过剩条件下PPARα和ERRγ的调节作用。 具体目标2是确定HFD诱导的节律性从头开始的生理后果 脂肪生成(DNL)和脂肪酸氧化(FAO)途径在整个肝脏脂肪代谢中。我们 已经确定了FAO的节律性比率与参与节律性表达的基因一致 粮农组织。为此，我将测定体内新生脂肪生成率，以解析其生理效应。 HFD增强DNL的节律性。此外，为了确定DNL和粮农组织之间的假定相互作用， 将检测在相同或不同的肝细胞中诱导SREBP和PPARα的情况以及SCAP的作用 (DNL的主要调节者)对喂养HFD的小鼠的FAO昼夜节律的敲除将进一步确定。 通过本提案中详述的创新和全面的研究战略，申请人Dr。 将接受生物信息学和代谢生理学技术方面的广泛培训，这些技术包括 对在顶尖学术机构从事新陈代谢和昼夜节律研究的职业至关重要。建议的选址 宾夕法尼亚大学的研究是一所最先进的机构，提供先进的技术 开展拟议研究所需的资源。赞助商米切尔·A·拉扎尔博士是一个世界- 著名的基因转录和代谢研究人员，将提供理想的协作环境 培训关博士，为从事新陈代谢研究做准备。这里提出的研究将有助于 解决与脂类合成代谢和分解代谢的反直觉和一致性上调有关的问题 HFD下的通路，并可能揭示与肝脂代谢紊乱相关的分子基础 有高营养的喂养。