Identifying genes required for digestive physiology and lipid metabolism

识别消化生理学和脂质代谢所需的基因

• 批准号: 10223272
• 负责人: STEVEN A FARBER
• 金额: $ 63.64万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223272
• 关键词: Acinetobacter; Address; Animals; Apolipoproteins B; Automobile Driving; Bacteria; Binding; Biological Assay; Blood Circulation; CREB1 gene; Calcium; Cardiovascular system; Cell physiology; Cells; Cellular Morphology; Chylomicrons; Consumption; Diabetes Mellitus; Dietary Fats; Dietary Fatty Acid; Digestion; Digestive Physiology; Distal; Endoplasmic Reticulum; Enterocytes; Enteroendocrine Cell; Enzymes; Epithelial Cells; Esters; Etiology; Fatty Acids; Fatty acid glycerol esters; Feedback; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Germ-Free; Gnotobiotic; Health; High Fat Diet; Hormones; Human; Image; Impairment; Incidence; Ingestion; Intestinal Absorption; Intestines; Knowledge; Larva; Lead; Lipase; Lipid Inclusion; Lipids; Lipolysis; Lipoproteins; Mediating; Metabolic Diseases; Methods; Mission; Molecular; Mus; Nonesterified Fatty Acids; Nutrient; Organ; Outcome; Pathway interactions; Process; Production; Reaction Time; Reporter; Research; Resistance; Resolution; Route; Sensory; Severities; Signal Pathway; System; Testing; Tissues; Transgenic Organisms; Triglycerides; United States National Institutes of Health; Up-Regulation; Work; Zebrafish; absorption; burden of illness; cost efficient; design; dietary; endoplasmic reticulum stress; enzyme pathway; gut microbiota; host microbiota; in vivo; in vivo imaging; inhibitor/antagonist; intestinal epithelium; lipid metabolism; microbial; microbiota; mortality; mutant; novel; particle; programs; response; tool; transcription factor; uptake

Intestinal absorption of dietary nutrients is an important process contributing to the etiology of multiple metabolic diseases in humans. An animal’s response to a high-fat meal requires coordination between digestive tissues and intestinal microbiota. Enterocytes (EC) are the absorptive cells of the intestine that prepare lipids for circulation to distal tissues in Apolipoprotein B (ApoB)-containing lipoproteins. Sensory enteroendocrine cells (EEC) communicate nutrient information to other cells and tissues via calcium- dependent hormone release. However, the transcriptional and signaling pathways mediating EC and EEC postprandial responses to a high-fat meal are unclear, and how microbiota influence these interactions is unknown. To address these knowledge gaps, our research team has pioneered the zebrafish system for studies of lipid metabolism and host-microbiota interaction. This includes (1) novel methods to image digestive organ lipid uptake, transport and storage, (2) the first reporter line to quantify the size and numbers of ApoB- containing lipoproteins from vanishing small amounts of material, (3) a fluorescent indicator of EEC activity that permits analysis of in vivo real-time responses to dietary nutrients, and (4) methods for cost-efficient gnotobiotic manipulation. Leveraging these tools for high-resolution in vivo imaging only possible in the larval zebrafish, we have uncovered a dynamic integrative pathway underlying EC, EEC, and microbial postprandial responses to dietary lipids. This includes early postprandial interactions in EC between a host transcription factor and the lipoprotein synthesis enzyme pathway, and late postprandial adaptive responses by EEC that are mediated by microbiota. The objective of this proposal is to define the molecular mechanisms underlying these EC and EEC postprandial responses to dietary lipid, and the specific steps controlled by microbiota. We will test the central hypothesis that microbiota promote lipolysis of dietary fat into fatty acids that are absorbed by EC leading to activation of a transcriptional program and synthesis of ApoB-containing lipoprotein particles, which are collectively perceived by EEC to alter their activity. This competitive renewal leverages long-standing partnerships between three field-leading labs with a powerful set of mutant and novel transgenic reporter lines developed during the prior funding period. The expected outcomes of the proposed research are expected to have a significant impact because they are likely to lead to new strategies for rationally manipulating EC, EEC, and microbiota interactions and responses to dietary fat which could be used to reduce incidence and severity of metabolic diseases in humans.

饮食营养素的肠道抽象是导致人类多种代谢疾病的病因的重要过程。动物对高脂餐的反应需要消化组织和肠道菌群之间的协调。肠上皮细胞（EC）是肠的吸收细胞，它们使脂质脂质用于循环至载脂蛋白B（APOB）含脂蛋白的远端组织。感觉肠内分泌细胞（EEC）通过钙依赖的雌激素释放将营养信息传达给其他细胞和组织。但是，介导EC和EEC后餐后反应的转录和信号通路尚不清楚，并且微生物群如何影响这些相互作用是未知的。为了解决这些知识差距，我们的研究团队率先开创了斑马鱼系统，用于研究脂质代谢和宿主 - 微生物群相互作用。这包括（1）图像图像消化器官脂质摄取，传输和存储的新方法，（2）量化含有少量材料的含量的大小和含脂蛋白的大小和数量的第一条记者线，（3）EEC活性的荧光指标，允许对饮食中的饮食中的饮食中的实时反应分析对饮食中的饮食养分率和成本（4）方法（4）。仅在幼虫斑马鱼中才能利用这些工具用于体内成像，我们发现了EC，EEC和微生物后餐后对饮食脂质的动态综合途径。这包括宿主转录因子与脂蛋白合成酶途径之间EC的早期餐后相互作用，以及由Microbiota介导的EEC晚期餐后自适应反应。该提案的目的是定义这些EC和EEC后餐后反应的分子机制，以及由微生物群控制的特定步骤。我们将检验一个中心假设，即菌群促进饮食脂肪的脂肪分解成脂肪酸，这些脂肪酸被EC吸收，从而导致转录程序的激活和含APOB的含APOB脂蛋白颗粒的合成，而EEC则被EEC统一认为改变其活性。这种有竞争力的更新利用了三个现场领导实验室之间的长期合作伙伴关系，该实验室具有强大的突变和新颖的转基因记者线，在上一期融资期间开发了。预计拟议研究的预期结果将产生重大影响，因为它们可能会导致合理操纵EC，EEC和微生物群相互作用的新策略，以及对饮食脂肪的反应，这些策略可用于减少人类代谢性疾病的发生率和严重性。