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

项目摘要 流行病学研究表明，营养过剩的人容易患上 代谢疾病，如2型糖尿病、心血管疾病、高血压和癌症。在现代 在当今社会，昼夜节律失调越来越被认为是代谢紊乱的危险因素。比如说， 夜班工人和有睡眠障碍的人患肥胖症，糖尿病， 以及相关的代谢疾病，类似于营养过剩的结果。然而，营养环境 对整体转录和表观基因组昼夜节律的影响还不清楚。这个目标 建议是了解营养过剩诱导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因子对脂质代谢的影响。 条件我的初步数据已经证明了小鼠肝脏中的整体转录重塑后， 高营养、高脂肪饮食（HFD）挑战。具体目标1是剖析 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ERR γ敲除小鼠模型的方法和最先进的全基因组方法将 可用于无偏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。 在整个肝脏脂质代谢中，脂肪生成（DNL）和脂肪酸氧化（FAO）途径。我们 已经确定FAO速率的节律性与参与基因的节律性表达一致， 粮农组织。在这个目标中，我将确定在体内的从头脂肪生成率，以解析出的生理效应， HFD增强DNL的节律性。此外，为了确定DNL和FAO的假定相互作用， 将检查相同或不同肝细胞中SREBP和PPARα的诱导，并且SCAP的作用 将进一步确定在HFD喂养的小鼠中，FAOs（DNL的主调节物）敲除对FAO的昼夜节律的影响。 通过创新和全面的研究策略，在这个建议中详细说明，申请人，博士。 Dongyin Guan将获得生物信息学和代谢生理学技术方面的广泛培训， 这对在顶级学术机构从事代谢和昼夜节律研究至关重要。拟建场址 宾夕法尼亚大学是一所最先进的研究机构，提供技术先进的 开展拟议研究所需的资源。发起人米切尔·A博士拉扎尔，是一个世界- 著名的基因转录和代谢研究人员，谁将提供理想的合作环境 培养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 解决脂质合成代谢和分解代谢的反直觉和一致性上调的相关性 HFD下的途径，并可能揭示肝脂质失调相关的分子基础 高营养喂养。

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.