integrin-mediated regulation of enterocyte lipid homeostasis

整合素介导的肠上皮细胞脂质稳态调节

• 批准号: 9156469
• 负责人: KAMRAN ATABAI
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-06 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156469
• 关键词: Behavior; Binding; Biological; Body Weight decreased; Caco-2 Cells; Cell surface; Cells; Chylomicrons; Coronary heart disease; Coupled; Data; Development; Dietary Fats; Endoplasmic Reticulum; Enterocytes; Epidermal Growth Factor; Family; Fatty Acids; Fatty acid glycerol esters; Food; Genes; Genetic Transcription; Goals; Grant; Health; Homeostasis; Hydrolysis; In Vitro; Ingestion; Intake; Integrin Binding; Integrin alphaVbeta3; Integrins; Intestinal Absorption; Intestines; Knowledge; Life; Ligands; Link; Lipid Mobilization; Lipids; Lipoproteins; Malabsorption Syndromes; Mediating; Mediator of activation protein; Mission; Mus; Nature; Nonesterified Fatty Acids; Nutrient; Obese Mice; Obesity; Oral; Organ; Organism; Outcome; Pathway interactions; Phosphorylation; Physiological; Process; Production; Proteins; Public Health; Regulation; Research; Role; Serum; Signal Pathway; Signal Transduction; Small Intestines; Source; Steatorrhea; Testing; Therapeutic; Toxic effect; Transcript; Transcriptional Regulation; Transgenic Mice; Treatment Efficacy; Triglycerides; United States National Institutes of Health; Work; absorption; base; disability; in vivo; innovation; lipid metabolism; milk fat globule; mouse model; new therapeutic target; novel; nutrient absorption; obesity treatment; receptor; response; small molecule inhibitor; therapeutic development; uptake

SUMMARY Intestinal absorption of dietary fats is important for the development of obesity and its complications. The long- term goal is to understand the role of the integrin family of cell surface matrix receptors in regulating intestinal nutrient absorption. The overall objective of this application is to elucidate the role of the αvβ3 and αvβ5 integrins in regulating small intestinal lipid homeostasis. The central hypothesis is that in response to ingestion of dietary fat, enterocytes secrete the integrin ligand Mfge8. Mfge8 then binds enterocyte αvβ3 and αvβ5 integrins activating a signaling pathway that increases the absorption of dietary fat coupled with synthesis of triglyceride (TG) in the endoplasmic reticulum and hydrolysis of TG in cytoplasmic lipid droplets. This hypothesis is based on data demonstrating that mice deficient in Mfge8 or the αvβ3 and αvβ5 integrins develop steatorrhea and in response to a dietary fat challenge absorb less fat, accumulate excess cytoplasmic lipid droplets and secrete less chylomicrons. The rationale for these studies is that delineating the role of the Mfge8-integrin axis in intestinal lipid absorption is necessary to understand the mechanisms by which enterocytes regulate lipoprotein production. This hypothesis will be tested through 3 specific aims: 1) Determining how nutrients induce enterocyte production of Mfge8 transcript and protein and the physiological role of the Mfge8 and the αvβ3 and αvβ5 integrins in absorption of dietary fat; 2) Determining the role of the αvβ3 and αvβ5 integrins in regulating hydrolysis of TG in enterocyte cytoplasmic lipid droplets; and 3) Determining the therapeutic potential of targeting the αvβ3 and αvβ5 integrins for the treatment of obesity. Aim 1 will examine transcriptional regulation of Mfge8 in differentiated Caco-2 cells and primary enterocytes, secretion of Mfge8 into the intestinal lumen in response to different nutrients, and identification of the cellular source of Mfge8 required for fat absorption through use of transgenic mice with enterocyte specific deletion of Mfge8 or Mfge8 deficient mice with enterocyte specific expression of Mfge8. Aim 2 will examine the mechanisms by which Mfge8 and the αvβ3 and αvβ5 integrins regulate hydrolysis of TG from lipid droplets using in vivo studies with integrin and Mfge8 deficient mice and in vitro studies with differentiated Caco-2 cells. Studies will determine how the Mfge8-integrin axis regulates subcellular localization and phosphorylation of lipolytic mediators. Aim 3 will test the therapeutic efficacy of oral inhibition of the αvβ3 and αvβ5 integrins in inducing weight loss in obese mice coupled with development of novel compounds with optimized potency and selectivity for blocking this pathway. The proposed research is innovative, in the applicant's opinion, because it identifies a mechanism for linking uptake of ingested dietary fats with hydrolysis of TG from cytoplasmic lipid droplets for chylomicron production. The proposed research is significant because it will expand the understanding of how the intestine absorbs and processes dietary fat for export. This knowledge has the potential to inform the development of therapeutics that can reduce obesity and postprandial lipemia.

概括 饮食脂肪的肠道吸收对于危险的fortant fortant fortant ots ATS并发症很重要。 术语目标是了解细胞表面基质受体的整合素家族在调节肠道中的作用 营养吸收。 整合小肠脂质稳态。 饮食脂肪，肠细胞分泌整联蛋白配体MFGE8。 整合素激活信号传导途径，该途径增加了与合成的致命性致命性致命的吸收 内质网中的甘油三酸酯（TG）和TG在细胞质中的水解 假设基于数据，证明小鼠在MFGE8或αVβ3和Vβ5整合素中的屈服 发展出脂肪性脂肪性，以应对饮食中的脂肪挑战会吸收较少的脂肪，从而积累过多的细胞质 脂肪液滴和分泌少花蛋。 肠道脂质吸收中的MFGE8-整合蛋白轴对于了解其机制是必要的 肠细胞调节脂蛋白的产生。 确定养分如何诱导MFGE8转录本的肠细胞产生以及潜在的蛋白质以及生理学 MFGE8和αVβ3和αVβ5整合在饮食脂肪中的作用； αVβ3和αVβ5整合在调节肠细胞细胞脂质液滴中TG的水解中； 确定靶向αVβ3和Vβ5整合素的治疗潜力 1将检查分化的Caco-2细胞和原代肠细胞中MFGE8的转录调控， 将MFGE8分泌到肠腔中，以响应不同的营养，并鉴定细胞 MFGE8的来源通过使用肠肠细胞规范缺失的转基因小鼠的脂肪吸收所需 MFGE8或MFGE8缺乏的小鼠具有MFGE8的肠肠细胞特异性表达。 MFGE8和αVβ3和αVβ5整合蛋白从脂质液滴调节Tg的液体的机制 使用整联蛋白和MFGE8缺乏小鼠的体内研究以及分化的Caco-2细胞的体外研究。 研究将MFGE8-整合蛋白轴如何调节亚细胞定位和磷酸化 脂肪分解介质3将测试αVβ3和αVβ5整合的治疗官员 肥胖小鼠的体重减轻以及新型综合效力的发展 申请人认为，阻止此途径的选择性是创新的 确定一种将摄入的饮食脂肪与细胞质脂质的Tg含水的摄取的机制 胆小物产生的液滴。 了解肠道如何吸收和处理饮食脂肪的出口。 有可能告知可以减少肥胖和餐后脂肪血症的治疗剂的发展。