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: 10618987
• 负责人: RAJAN SINGH
• 金额: $ 14.68万
• 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/10618987
• 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; LDL Cholesterol Lipoproteins; Laboratories; Lesion; Lipoproteins; Liver; Low Density Lipoprotein Receptor; LoxP-flanked allele; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Molecular; Molecular Target; Morbidity - disease rate; Mus; NOS2A gene; Nonesterified Fatty Acids; Ornithine; Pathway interactions; Patients; Peptides; 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; fibroblast growth factor 21; genetic approach; genetic variant; human subject; inhibitor; insight; lipid metabolism; lipidomics; lipoprotein cholesterol; metabolomics; mortality; mouse genetics; mouse model; novel; novel therapeutics; overexpression; p38 Mitogen Activated Protein Kinase; pharmacologic; 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.

摘要 动脉粥样硬化是绝大多数心血管疾病(CVD)的根本原因，并构成巨大的 对公众健康的威胁。激活生热脂肪细胞可降低胆固醇水平并保护机体免受 动物模型中的动脉粥样硬化。血脂异常患者的生热脂肪细胞活性降低 以高甘油三酯(TG)、低血浆高密度脂蛋白胆固醇(HDLC)为特征 降低解偶联蛋白1(UCP1)的表达。在老鼠和人类身上的这些发现 强调生热脂肪细胞计划诱导剂作为潜在治疗靶点的重要性 血脂异常和心血管疾病的治疗。我们已发表的和初步的数据表明，卵泡抑素(Fst) 不仅在脂肪细胞褐变中发挥重要作用，而且在调节甘油三酯和总胆固醇的脂蛋白代谢中也起着重要作用 胆固醇(TC)和高密度脂蛋白胆固醇(HDLC)水平。在这个提案中，我们将测试我们的中心假设，即FST诱导 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LDLR-/-小鼠的作用 I)脂肪褐变、血浆脂蛋白、甘油三酯和总胆固醇水平，ii)组织(脂肪、主动脉和肝脏)、血浆 代谢产物和iii)饮食诱导的血脂异常和动脉粥样硬化形成过程中的基因表达。效果 Fst对褐变、脂蛋白代谢和动脉粥样硬化进展的瞬时损失将在 MPCSK9注射Fstfl/fl/CreAdQ小鼠。目标2：我们将确定FST授予的分子机制 促进褐变和抗动脉粥样硬化的作用。我们将测试精氨酸酶1(Arg 1)/β肾上腺素能受体 (β-AR)/p38MAPK/FGF21信号通路在Fst诱导的促褐变和抗动脉粥样硬化中的作用 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 利用动脉粥样硬化杂交鼠多样性小组(HMDP)识别FST调控关键基因的系统遗传学方法 基因和代谢物。我们将进行全面的RNA序列分析，组织和血浆 代谢物分析与药物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 动脉硬化。使用Fst蛋白/肽抑制动脉粥样硬化的发展是一种有吸引力的治疗方法 大道。本项目成功完成后获得的数据为治疗药物设计提供了理论依据 用于治疗动脉粥样硬化，并使我们能够提交竞争激烈的RO1类拨款申请。