Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis

卵泡抑素对动脉粥样硬化进展过程中能量和脂质代谢的调节

• 批准号: 10412836
• 负责人: RAJAN SINGH
• 金额: $ 14.88万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412836
• 关键词: 3T3-L1 Cells; Adipocytes; Adipose tissue; Adult; Animal Model; Antiatherogenic; Aorta; Applications Grants; Area; Arginine; Arterial Fatty Streak; Atherosclerosis; Cardiovascular Diseases; Cholesterol; Data; Data Correlations; Data Set; Dependovirus; Development; Diet; Drug Design; Dyslipidemias; Energy Metabolism; FGF21 gene; Follistatin; Gene Chips; Gene Expression; Generations; Genes; Genetic; Grant; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Homeostasis; Human; Hybrids; Immunoprecipitation; Laboratories; Lesion; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; LoxP-flanked allele; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Molecular; Molecular Target; Morbidity - disease rate; Mus; NOS2A gene; Nonesterified Fatty Acids; Ornithine; Pathway interactions; Patients; Peptides; Pharmacology; Phenylalanine; Phosphorylation; Plasma; Play; Property; Proprotein Convertases; Proteins; Public Health; Publishing; RNA Sequence Analysis; Receptors, Adrenergic, beta-1; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Thermogenesis; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; Triglycerides; Viral Vector; Work; adiponectin; arginase; beta-adrenergic receptor; enzyme pathway; genetic approach; genetic variant; human subject; inhibitor; insight; lipid metabolism; lipidomics; lipoprotein triglyceride; metabolomics; mortality; mouse genetics; mouse model; novel; novel therapeutics; overexpression; p38 Mitogen Activated Protein Kinase; programs; promoter; protein expression; reverse cholesterol transport; therapeutic target; therapy design; transcription factor; transcriptome sequencing; transcriptomics; uncoupling protein 1

Abstract Atherosclerosis is the underlying cause of great majority of cardiovascular diseases (CVD) and poses a great threat to public health. Activation of thermogenic adipocytes reduces cholesterol levels and protects against atherosclerosis in animal models. Lower thermogenic adipocyte activity in dyslipidemic patients has been characterized by high plasma triglycerides (TG), low plasma high density lipoprotein cholesterol (HDL-C) concentration and lower uncoupling protein 1 (UCP1) expression. These findings in mice and humans underscore the importance of inducers of the thermogenic adipocyte program as potential therapeutic targets for the treatment of dyslipidemia and CVD. Our published and preliminary data demonstrate that follistatin (Fst) plays an important role not only in adipocyte browning but also in lipoprotein metabolism to regulate TG, total cholesterol (TC), and HDL-C levels. In this proposal, we will test our central hypothesis that Fst-induced adipose browning protects against the development of atherosclerosis. We will test our hypothesis under these Specific Aims: Aim 1: We will determine the role of Fst in adipose browning, lipoprotein metabolism and development of atherosclerosis. We will determine the effects of Fst tissue and systemic overexpression using mouse low density lipoprotein receptor (LDLR)-deficient WT and adipose-specific transgenic (FstAdQTg ) mice, and adeno-associated virus 1 (AAV1)-FST344 injected LDLR-/- mice respectively to determine the role of Fst on i) adipose browning, plasma lipoprotein, TG, and TC levels, ii) tissue (adipose, aorta, and liver), plasma metabolites and iii) gene expression during diet-induced development of dyslipidemia and atherosclerosis. Effect of transient loss of Fst on browning, lipoprotein metabolism and atherosclerosis progression will be analyzed in mPCSK9 injected Fstfl/fl / CreAdQ mice. Aim 2: We will determine the molecular mechanisms by which Fst confer the pro-browning and anti-atherogenic effects. We will test whether arginase 1 (Arg 1)/beta-adrenergic receptor (β-AR)/ p38MAPK/FGF21 signaling pathway confer Fst-induced pro-browning and antiatherogenic action in the three animal models. We will utilize gene aortic lesion and gene metabolite correlation dataset obtained from system genetics approach of atherosclerosis hybrid mouse diversity panel (HMDP) to identify key Fst-regulated genes and metabolites. We will perform comprehensive RNA-sequence analysis, and tissue and plasma metabolite analysis combined with pharmacological inhibition studies to identify novel genes and metabolites involved during Fst-induced adipose browning and its anti-atherogenic actions. Our proposed studies will provide significant novel insights into the pro-browning and anti-atherogenic role of Fst and identify key molecular targets involved in favorably altering lipoprotein metabolism and the development of atherosclerosis. Inhibition of atherosclerosis development by using Fst protein/peptide is an attractive therapeutic avenue. Data obtained after successful completion of this project provide rationale for therapeutic drug design for the treatment of atherosclerosis and enable us to submit highly competitive RO1-like grant applications.

抽象的 动脉粥样硬化是绝大多数心血管疾病 (CVD) 的根本原因，并造成很大的影响。 对公众健康的威胁。生热脂肪细胞的激活可降低胆固醇水平并防止 动物模型中的动脉粥样硬化。血脂异常患者的产热脂肪细胞活性较低 其特点是血浆甘油三酯（TG）高、血浆高密度脂蛋白胆固醇（HDL-C）低 浓度和降低解偶联蛋白 1 (UCP1) 表达。这些在小鼠和人类身上的发现 强调生热脂肪细胞程序诱导剂作为潜在治疗靶点的重要性 血脂异常和CVD的治疗。我们已发表的初步数据表明，卵泡抑素 (Fst) 不仅在脂肪细胞褐变中发挥重要作用，而且在脂蛋白代谢中发挥重要作用，以调节 TG、总脂 胆固醇 (TC) 和 HDL-C 水平。在这个提案中，我们将测试我们的中心假设，即 Fst 诱导的 脂肪褐变可防止动脉粥样硬化的发展。我们将在这些条件下检验我们的假设 具体目标： 目标 1：我们将确定 Fst 在脂肪褐变、脂蛋白代谢和 动脉粥样硬化的发展。我们将使用以下方法确定 Fst 组织和系统过度表达的影响 小鼠低密度脂蛋白受体 (LDLR) 缺陷型 WT 和脂肪特异性转基因 (FstAdQTg) 小鼠， 和腺相关病毒1（AAV1）-FST344分别注射LDLR-/-小鼠以确定Fst对 i) 脂肪褐变、血浆脂蛋白、TG 和 TC 水平，ii) 组织（脂肪、主动脉和肝脏）、血浆 代谢物和iii)饮食诱导的血脂异常和动脉粥样硬化发展过程中的基因表达。影响 Fst 短暂丧失对褐变、脂蛋白代谢和动脉粥样硬化进展的影响将在 mPCSK9 注射 Fstfl/fl / CreAdQ 小鼠。目标 2：我们将确定 Fst 赋予的分子机制 促褐变和抗动脉粥样硬化作用。我们将测试精氨酸酶 1 (Arg 1)/β-肾上腺素能受体是否 (β-AR)/ p38MAPK/FGF21 信号通路赋予 Fst 诱导的促褐变和抗动脉粥样硬化作用 三个动物模型。我们将利用从以下来源获得的基因主动脉病变和基因代谢物相关数据集 动脉粥样硬化杂种小鼠多样性小组（HMDP）的系统遗传学方法识别关键的Fst调节 基因和代谢物。我们将进行全面的 RNA 序列分析以及组织和血浆 代谢分析与药理学抑制研究相结合，以确定新基因和代谢物 参与 Fst 诱导的脂肪褐变及其抗动脉粥样硬化作用。 我们提出的研究将为 Fst 的促褐变和抗动脉粥样硬化作用提供重要的新见解 并确定参与有利改变脂蛋白代谢和发展的关键分子靶点 动脉粥样硬化。使用 Fst 蛋白/肽抑制动脉粥样硬化发展是一种有吸引力的治疗方法 大街。该项目成功完成后获得的数据为治疗药物设计提供了理论基础 用于治疗动脉粥样硬化，并使我们能够提交极具竞争力的类似 RO1 的拨款申请。