Investigating the Novel Roles of FFAR4 in Foam Cell Formation and Atherosclerosis

研究 FFAR4 在泡沫细胞形成和动脉粥样硬化中的新作用

• 批准号: 10676531
• 负责人: Gage M Stuttgen
• 金额: $ 4.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2026-04-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676531
• 关键词: ATP binding cassette transporter 1; Adipocytes; Agonist; Anti-Inflammatory Agents; Aorta; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; Biological Process; Blood specimen; Bone Marrow Transplantation; CD36 gene; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cholesterol; Cytoplasm; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Experimental Designs; Fasting; Foam Cells; Future; G-Protein-Coupled Receptors; Harvest; Homeostasis; Image; Incubated; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lipids; Literature; Low Density Lipoprotein Receptor; Macrophage; Measures; Mediating; Metabolic; Mus; Nonesterified Fatty Acids; Outcome; Pathway interactions; Peritoneal Macrophages; Phosphorylation; Physiological; Play; Prevention; Process; Property; Proteins; Publishing; Research; Role; Severities; Signal Pathway; Signal Transduction; Testing; United States; Unsaturated Fatty Acids; Wild Type Mouse; atheroprotective; cardioprotection; cholesterol transporters; cytokine; design; experimental study; immune activation; in vivo; insulin sensitivity; lipid biosynthesis; migration; new therapeutic target; novel; obesity prevention; oxidized low density lipoprotein; prevent; receptor; therapeutic target; transcription factor; uptake; western diet

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States. Atherosclerosis, a major cause of CVD, is an inflammatory disease resulting from the build-up of cholesterol in plaque along the artery walls. These plaques are formed by accumulation of macrophage foam cells as an inflammatory response to oxidized low-density lipoprotein (oxLDL) in damaged endothelial cells. Free fatty acid receptor 4 (FFAR4), also known as G-protein coupled receptor 120 (GPR120), is a long-chain unsaturated fatty acid receptor expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. While FFAR4 is best known for its protective role in preventing obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the prevention of atherosclerosis and CVD. Given FFAR4’s importance in anti-inflammatory signaling and high expression levels in macrophages, we designed experiments to test the hypothesis that FFAR4 plays a cardioprotective role by preventing pathways that lead to atherosclerosis. These experiments will require macrophages harvested from wild-type and FFAR4-knockout mice, and in some cases, macrophages treated with FFAR4 agonists. In Aim 1, we will investigate the effects of FFAR4 deficiency on macrophage foam cell formation. Specifically, we will determine whether FFAR4 deficiency increases oxLDL uptake (Aim 1.1), decreases cholesterol efflux (Aim 1.2), and decreases macrophage migration (Aim 1.3). In Aim 2, we will investigate the signaling mechanisms utilized by FFAR4 to protects against foam cell formation and test the hypothesis that canonical Gaq/11 FFAR4 signaling reduces cholesterol uptake and promotes cholesterol efflux by inhibiting the transcription factor PPARg. In Aim 3, we will investigate the physiological role of FFAR4 in atherosclerosis. Aim 3.1 will examine how FFAR4 deficiency in vivo impacts lipid levels and circulating inflammatory cytokines. Aim 3.2 will assess atherosclerotic lesion size differences and immune cell activation status in the aorta of LDLR-/- mice following transplantation of bone marrow from FFAR4+/+ or FFAR4-/- mice. The outcomes of these proposed studies will uncover the biological functions of FFAR4 and mechanisms that underlie how FFAR4 protects against macrophage foam cell formation, a hallmark of atherosclerosis. Ultimately, our combined current and future studies may identify FFAR4 as a novel therapeutic target for atherosclerosis.

项目总结/摘要 心血管疾病（CVD）是美国的主要死亡原因。动脉粥样硬化，一个主要原因 心血管疾病是一种炎症性疾病，由胆固醇在动脉壁沿着斑块中积聚引起。 这些斑块是由巨噬细胞泡沫细胞的积累形成的，作为对氧化的炎症反应。 低密度脂蛋白（oxLDL）在受损的内皮细胞。游离脂肪酸受体4（FFAR 4），也称为 G蛋白偶联受体120（GPR 120）是一种长链不饱和脂肪酸受体，在人乳腺癌组织中表达。 脂肪细胞、内皮细胞和巨噬细胞。FFAR 4的激活有助于维持代谢稳态， 调节脂肪生成、胰岛素敏感性和炎症。虽然FFAR 4以其保护作用而闻名， 在预防肥胖和糖尿病方面，最近的研究表明，FFAR 4也可能发挥重要作用， 预防动脉粥样硬化和心血管疾病的作用。鉴于FFAR 4在抗炎信号传导中的重要性， 由于FFAR 4在巨噬细胞中的高表达水平，我们设计了实验来检验FFAR 4在巨噬细胞中发挥作用的假设。 通过阻止导致动脉粥样硬化的途径发挥心脏保护作用。这些实验需要 从野生型和FFAR 4敲除小鼠收获的巨噬细胞，并且在一些情况下， FFAR 4激动剂。目的1：研究FFAR 4缺陷对巨噬细胞泡沫细胞的影响 阵具体来说，我们将确定FFAR 4缺乏是否会增加oxLDL摄取（目标1.1）， 降低胆固醇流出（目标1.2），并降低巨噬细胞迁移（目标1.3）。在目标2中，我们将 研究FFAR 4用于防止泡沫细胞形成的信号传导机制，并测试FFAR 4对泡沫细胞形成的影响。 经典Gaq/11 FFAR 4信号传导通过以下方式降低胆固醇摄取并促进胆固醇流出的假设 抑制转录因子PPARg。在目标3中，我们将研究FFAR 4在以下方面的生理作用： 动脉粥样硬化目的3.1将研究体内FFAR 4缺陷如何影响脂质水平和循环 炎性细胞因子目的3.2将评估动脉粥样硬化病变大小差异和免疫细胞活化 在移植来自FFAR 4 +/+或FFAR 4-/-小鼠的骨髓后LDLR-/-小鼠的主动脉中的状态。的 这些研究的结果将揭示FFAR 4的生物学功能和机制， 这是FFAR 4如何防止巨噬细胞泡沫细胞形成的基础，巨噬细胞泡沫细胞形成是动脉粥样硬化的标志。最后， 我们结合当前和未来的研究可能会将FFAR 4确定为动脉粥样硬化的新治疗靶点。