Mechanisms of cytoplasmic lipid droplet regulation in the intestine

肠道细胞质脂滴调节机制

• 批准号: 9121995
• 负责人: Meredith H Wilson
• 金额: $ 5.43万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121995
• 关键词: Accounting; Acute; Address; Adipocytes; Autophagocytosis; Biological Assay; Biological Models; Blood; Blood Circulation; Brain; Cardiovascular Diseases; Cell Line; Cholesterol Esters; Chronic; Chylomicrons; Data; Detection; Development; Dietary Fats; Dietary Fatty Acid; Enterocytes; Enzymes; Epithelial Cells; Esthesia; Exhibits; Exposure to; Fatty acid glycerol esters; Fishes; Goals; High Fat Diet; Hour; Human; Hypertriglyceridemia; Individual; Ingestion; Intestines; Label; Larva; Lipase; Lipids; Lipolysis; Lipoproteins; Maintenance; Mediating; Metabolic syndrome; Methods; Modeling; Mus; Oral; Organelles; Phospholipids; Population; Prevention; Prevention strategy; Process; Production; Proteins; Regulation; Risk Factors; Role; Serum; Source; Surface; System; Taste Buds; Taste Perception; Testing; Transgenic Organisms; Triglycerides; Variant; Work; Zebrafish; absorption; base; design; disorder risk; feeding; in vivo; in vivo imaging; lipid metabolism; monolayer; novel; perilipin; protein expression; public health relevance; relating to nervous system; research study; response; tool

 DESCRIPTION (provided by applicant): Elevated postprandial levels of triglyceride-rich lipoproteins (TRL) in the circulation are a risk factor for cardiovascular disease. Following a meal, chylomicrons produced by the intestine contribute prominently to circulating triglyceride (TG) levels, and production is primarily determined by the amount of fat ingested and absorbed. However, growing evidence suggests the intestine can actively regulate the rate of postprandial chylomicron production in part through transient TG storage and delayed export. Further, individuals with metabolic syndrome often exhibit hyperchylomicronemia. Thus, misregulation of intestinal TG storage and turnover likely contributes to disease risk. Intestinal enterocytes absorb and package dietary fatty acids into TG that is exported via chylomicrons or stored in cytoplasmic lipid droplets (LD). LDs are subcellular organelles composed of a core of TG and cholesterol esters surrounded by a monolayer of phospholipids and a variety of proteins, including perilipins. Intestinal LDs are dynamic storage compartments; they increase in number and size in the hours following a high-fat meal, but are nearly depleted 12-14 hours later in the absence of another meal. However, if a subsequent meal is consumed before the stored TG is depleted, it is rapidly exported in chylomicrons, suggesting that LD turnover is regulated. Despite the implications of intestinal LD regulation on postprandial serum TG levels, the mechanisms governing enterocyte LD regulation are poorly characterized. The overall goal of this proposal is to elucidate the cellular mechanisms regulating the maintenance and turnover of intestinal LDs following both an acute high-fat meal and in response to re- feeding. These studies will capitalize on the powerful transgenic and in vivo imaging opportunities afforded by the zebrafish model vertebrate system. Aim 1 of this proposal will determine whether LDs in enterocytes undergo rapid lipolysis by neutral lipases in response to re-feeding or are degraded by autophagy-mediated lipolysis. In Aim 2, the role of the LD-associated protein perilipin-2 in regulating intestinal LD storage and turnover will be explored. Human variants of perilipin-2 that are associated with favorable lipoprotein profiles will be evaluated to determine whether they alter intestinal LD dynamics. Aim 3 will establish whether zebrafish detect fat as a taste sensation and if this results in neural activation that is sufficient to elicit LD breakdown and chylomicron release in the fish, as has been suggested by human studies. Understanding intestinal regulation of lipid storage and lipoprotein production is imperative for development of strategies for the prevention and treatment of hypertriglyceridemia. Collectively, the proposed experiments will elucidate the cellular mechanisms regulating the storage and turnover of lipid in the intestine, produce novel methods and tools to study LD dynamics in vivo, and establish whether the zebrafish is a valid model to address how the brain communicates fat taste detection to intestinal enterocytes.

 描述（由适用提供）：循环中富含甘油三酸酯脂蛋白（TRL）的餐后水平升高是心血管疾病的危险因素。一顿饭后，肠产生的酪蛋白促进了循环甘油三酸酯（TG）水平，产生主要由摄入和吸收的脂肪量确定。然而，越来越多的证据表明，肠道可以通过瞬时TG存储和延迟出口来积极调节餐后乳糜微粒的产生率。此外，患有代谢综合征的个体通常暴露于高麦芽综合血症。这是肠道TG存储和周转率的正调可能导致疾病风险。肠肠细胞吸收并包装饮食中的脂肪酸进入TG，该脂肪酸通过乳糜微粒出口或存储在细胞质脂质液滴（LD）中。 LDS是由TG的核心和胆固醇酯组成的亚细胞细胞器，周围是磷脂的单层和各种蛋白质，包括佩里肽。肠LDS是动态存储室；在高脂餐后的几个小时内，它们的数量和大小增加，但在没有另一顿饭的情况下，它们几乎被耗尽了12-14小时。但是，如果在储存的TG耗尽之前消耗了随后的餐点，则将其迅速以乳糜微粒出口，这表明LD周转率受到调节。尽管肠道LD调节对餐后血清TG水平有影响，但管理肠球菌调节的机制的表征很差。该提案的总体目标是阐明细胞机制调节急性高脂餐后肠LDS的维持和转换，并响应重新喂养。这些研究将利用斑马鱼模型脊椎动物系统提供的强大转基因和体内成像机会。该提案的目标1将确定肠细胞中的LDS是通过中性脂肪酶响应重新喂养而快速脂肪分解，还是会因自噬介导的脂肪溶解而降解。在AIM 2中，将探讨与LD相关蛋白Peripin-2在调节肠道储存和周转中的作用。将评估与有利的脂蛋白谱相关的perilipin-2的人类变体，以确定它们是否改变了肠道LD动力学。 AIM 3将确定斑马鱼是否将脂肪视为味觉感觉，并且这是否导致神经激活足以引起鱼类中的LD分解和乳糜微粒释放，正如人类研究所表明的那样。了解脂质储存和脂蛋白产生的肠道调节对于制定预防和治疗高甘油三酯血症的策略至关重要。总的来说，提出的实验将阐明肠道中脂质储存和周转的细胞机制，生成新的方法和工具来研究体内的LD动力学，并确定斑马鱼是否是一种有效的模型，以解决脑部如何将脂肪的脂肪检测到肠道肠肠细胞。