Saturated Fatty Acid-induced Autophagy in Vascular Endothelium

饱和脂肪酸诱导血管内皮自噬

• 批准号: 9105963
• 负责人: Jeonga Kim
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105963
• 关键词: Acetylcholine; Address; Affect; Autophagocytosis; Autophagosome; Biological Availability; Blood Vessels; Blood flow; Body Weight; Cardiovascular Diseases; Catabolic Process; Cell Death; Cell Survival; Cells; Ceramides; Chronic; Communication; Data; Deposition; Dyslipidemias; Endothelial Cells; Energy Metabolism; Equilibrium; Exhibits; Fat-Restricted Diet; Fatty acid glycerol esters; Functional disorder; Genes; Glucose; Glucose Intolerance; Goals; High Fat Diet; Homeostasis; Hormones; Impairment; In Vitro; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; Lead; Lipids; Lysosomes; Membrane; Mesentery; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mus; Nutrient; Obesity; Organ; Organelles; Oxidative Stress; Oxygen; Pathway interactions; Pharmacological Treatment; Phenotype; Physiology; Play; Process; Production; Proteins; Recycling; Role; Saturated Fatty Acids; Skeletal Muscle; Small Interfering RNA; Stress; Structure; Syndrome; Testing; Tissues; Vascular Endothelium; Vasodilator Agents; Vasomotor; arteriole; blood glucose regulation; blood pressure regulation; endoplasmic reticulum stress; endothelial dysfunction; feeding; glucose metabolism; hemodynamics; impaired glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin signaling; knock-down; lipid metabolism; mitochondrial dysfunction; new therapeutic target; novel; nutrient metabolism; prevent; public health relevance

 DESCRIPTION (provided by applicant): Obesity is associated with ectopic deposition of fats which lead to lipotoxicity and chronic inflammation in various tissues. The long term goal of this study is to understand the mechanisms by which saturated fatty acid (SFA) induce endothelial dysfunction and its consequences in metabolic and cardiovascular disorders. Macroautophagy (hereafter autophagy) is initiated by the nucleation of membrane-like structure and encloses cargo (proteins, lipid, and organelles) in membranous structure (autophagosome), and subsequently the autophagosome fuses with lysosome forming autolysosome, in which final degradation of cargo material occurs. When the equilibrium between the autophagosome formation and degradation is not maintained, cells undergo stressful conditions that result in cellular damage, dysfunction, and cell death. We observed that SFA induces impaired lysosomal degradation (inhibition of autophagic flux). Cells treated with SFA show increased lipid droplets and pro-inflammatory responses that are associated with inhibition of autophagic flux. We recently generated endothelial specific autophagy gene 7 knockout mice (ATG7-EndKO) to examine the role of endothelial autophagy in endothelial function and nutrient metabolism. ATG7-EndKO mice fed low fat diet do not exhibit impaired glucose tolerance. However, high fat diet (HFD) fed ATG7-EndKO mice exhibit impaired glucose tolerance when compared with control HFD-fed mice. From these results, we hypothesized that endothelial autophagy plays a protective role in SFA-induced endothelial dysfunction and metabolic disorders. To address this hypothesis, we propose to test the following three specific aims. The first aim is to determine the mechanisms by which SFAs impair autophagic flux. We will identify the pathway(s) contributing to SFA-induced impairment of authopagic flux. The second aim is to determine whether impaired autophagy contributes to SFA-induced endothelial dysfunction. The goal of this aim is to understand the role of endothelial autophagy in NO bioavailability. The thir aims to determine whether impaired autophagy contributes to HFD- induced insulin resistance and dyslipidemia in vivo. The results will broaden the knowledge of the pathophysiological consequences of impaired endothelial autophagy in normal and metabolically stressed conditions. Accomplishment of these aims will contribute to understanding the novel mechanisms for SFA- induced endothelial dysfunction, and the role of endothelial autophagy in endothelial function and metabolic homeostasis. Thus, the results may help us to develop a novel therapeutic target to prevent and/or treat obesity-associated vascular complications and metabolism.

 描述（由申请人提供）：肥胖与脂肪异位沉积有关，导致各种组织中的脂毒性和慢性炎症。本研究的长期目标是了解饱和脂肪酸（SFA）诱导内皮功能障碍的机制及其在代谢和心血管疾病中的后果。大自噬（Macroautophagy，以下称为自噬）是由膜样结构的成核引发的，并将货物（蛋白质、脂质和细胞器）包封在膜结构（自噬体）中，随后自噬体与溶酶体融合形成自溶酶体，在自溶酶体中发生货物物质的最终降解。当不能维持自噬体形成和降解之间的平衡时，细胞经历导致细胞损伤、功能障碍和细胞死亡的应激条件。我们观察到，SFA诱导受损的溶酶体降解（抑制自噬通量）。用SFA处理的细胞显示增加的脂滴和促炎反应，其与自噬通量的抑制相关。我们最近产生了内皮特异性自噬基因7敲除小鼠（ATG 7-EndKO），以研究内皮细胞自噬在内皮功能和营养代谢中的作用。喂食低脂饮食的ATG 7-EndKO小鼠未表现出葡萄糖耐量受损。然而，与对照HFD喂养的小鼠相比，高脂肪饮食（HFD）喂养的ATG 7-EndKO小鼠表现出葡萄糖耐量受损。根据这些结果，我们假设内皮细胞自噬在SFA诱导的内皮功能障碍和代谢紊乱中起保护作用。为了解决这一假设，我们建议测试以下三个具体目标。第一个目的是确定SFAs损害自噬通量的机制。我们将确定导致SFA诱导的自显影通量受损的途径。第二个目的是确定受损的自噬是否有助于SFA诱导的内皮功能障碍。本研究的目的是了解内皮细胞自噬在NO生物利用度中的作用。本研究的目的是确定受损的自噬是否有助于体内HFD诱导的胰岛素抵抗和血脂异常。这些结果将拓宽在正常和代谢应激条件下受损的内皮细胞自噬的病理生理后果的知识。这些目标的实现将有助于理解SFA诱导的内皮功能障碍的新机制，以及内皮自噬在内皮功能和代谢稳态中的作用。因此，这些结果可能有助于我们开发一种新的治疗靶点，以预防和/或治疗肥胖相关的血管并发症和代谢。