The Role of DENND5B in Dietary Lipid Absorption

DENND5B 在膳食脂质吸收中的作用

• 批准号: 10661074
• 负责人: Scott M Gordon
• 金额: $ 51.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661074
• 关键词: AGFG1 gene; Acute; Address; Affect; Apolipoproteins B; Atherosclerosis; Autophagocytosis; Biogenesis; Bioinformatics; Body Composition; Body mass index; Cardiometabolic Disease; Cardiovascular Diseases; Cell membrane; Cells; Chylomicrons; Circulation; Co-Immunoprecipitations; Complex; Conscious; Data; Data Set; Diet; Dietary Fats; Dyslipidemias; Enterocytes; Equilibrium; Esterification; Exhibits; Fasting; Fat-Soluble Vitamin; Fatty acid glycerol esters; Fistula; Foundations; Genes; Golgi Apparatus; Guanine Nucleotide Exchange Factors; Health; High Fat Diet; Homeostasis; Human; In Vitro; Ingestion; Insulin Resistance; Intestinal Absorption; Intestinal Secretions; Intestines; Knowledge; Link; Lipids; Lipolysis; Lipoproteins; Literature; Lymph; Maintenance; Mass Spectrum Analysis; Measurement; Measures; Membrane Fusion; Metabolic; Metabolism; Methods; Mission; Mitochondria; Modeling; Mucous Membrane; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organism; Particle Size; Pathway interactions; Peripheral; Plasma; Play; Process; Proteins; Publishing; Regulation; Resistance; Risk Factors; Role; Secretory Vesicles; Sucrose; Tissues; Tracer; Transmembrane Transport; Triglycerides; United States National Institutes of Health; Variant; Very low density lipoprotein; Wild Type Mouse; Work; absorption; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; cell type; crosslink; dietary; exome sequencing; experimental study; gene network; gene regulatory network; improved; insight; intestinal epithelium; lipid metabolism; mouse model; novel; particle; response; single-cell RNA sequencing; trafficking; transcriptome; uptake

Project Summary Postprandial plasma triacylglyceride levels are independently associated with risk of cardiovascular disease. The intestine plays a key role in the regulation of dietary triacylglyceride absorption by packaging and secreting lipids in chylomicron particles. The intracellular steps of chylomicron biogenesis and transport have been fairly well described, however, there is a significant gap in our understanding of the mechanism for the final steps of chylomicron secretion by enterocytes, specifically post-Golgi transport and secretion. We recently identified a protein that plays a critical role in this pathway, DENND5B. Our newly generated Dennd5b-/- mouse demonstrates an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. Dennd5b-deficient mice are resistant to diet-induced: obesity, changes in plasma lipids, and atherosclerosis. In humans, exome sequencing studies reveal that a common DENND5B variant is correlated with body mass index. These studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent influence on body composition and peripheral lipoprotein metabolism. The overall objective of this proposal is to gain fundamental knowledge about the process of dietary lipid absorption by the intestine and to examine the impact of this process on systemic metabolic health. This objective aligns well with the NIH mission to seek fundamental knowledge about living systems and to apply this knowledge to enhance health. The Specific Aims of this proposal use our novel mouse model and in vitro experiments to examine the mechanistic role of DENND5B in the intestine and its systemic metabolic effects. Aim 1 will quantify the impact of Dennd5b on dietary lipid absorption and generate a comprehensive spatial single-cell RNAsequencing data set for examination of gene networks that participate in regulation of dietary lipid absorption. Aim 2 will examine the mechanism underlying Dennd5b action in CM transport. Furthermore, this aim will use mass spectrometry and interactomics analysis to expand our understanding of this process by identifying other interacting proteins which may form a complex to facilitate chylomicron secretion by the intestine. Aim 3 will determine the impact of Dennd5b on enterocyte metabolic function and peripheral lipid metabolism. Successful completion of this proposal will fill a significant knowledge gap in the process of dietary lipid absorption. This work will advance the field by providing mechanistic details for a key step in chylomicron secretion that can affect systemic lipid homeostasis and metabolic health.

项目摘要 餐后血浆三酰基甘油三酸酯水平与心血管风险独立相关 疾病。肠在调节饮食三酰基甘油酸酯吸收中起着关键作用 包装和分泌脂肪颗粒颗粒。乳糜微粒的细胞内步骤 生物发生和运输已经得到很好的描述，但是，我们的差距很大 了解肠球菌分泌乳糜微粒的最终步骤的机制，特别是 高尔基后运输和分泌。我们最近确定了一种在此中起着关键作用的蛋白质 dennd5b的途径。我们新生成的dennd5b - / - 鼠标展示了这一点的重要作用 高尔基体中的基因到乳糜微粒分泌囊泡的质膜转运。 DENND5B缺陷小鼠 对饮食引起的抗性：肥胖，血浆脂质的变化和动脉粥样硬化。在人类中，外显子 测序研究表明，常见的DEND5B变体与体重指数相关。这些 研究确定了DENND5B在后高尔基乳糜微粒分泌中的重要作用，随后 对人体成分和外周脂蛋白代谢的影响。总体目标 建议是获得有关肠道饮食脂质吸收过程的基本知识 并检查该过程对系统性代谢健康的影响。这个目标与 NIH的使命是寻求有关生活系统的基本知识，并将这些知识应用于 增强健康。该提案的具体目的使用我们的新型鼠标模型和体外 检验DENND5B在肠及其全身代谢中的机械作用的实验 效果。 AIM 1将量化DENND5B对饮食脂质吸收的影响并产生A 全面的空间单细胞RNasequencing数据集用于检查基因网络 参与饮食脂质吸收的调节。 AIM 2将检查基础机制 CM运输中的DENND5B动作。此外，此目标将使用质谱和互动组学 分析通过识别其他相互作用的蛋白质来扩展我们对这一过程的理解 形成一种复合物，以促进肠道的乳糜微粒分泌。 AIM 3将决定 DENND5B在肠肠细胞代谢功能和外周脂质代谢上。成功完成 该建议将填补饮食脂质吸收过程中的显着知识差距。这项工作将 通过提供机械细节来推动该领域 系统性脂质稳态和代谢健康。