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

项目摘要/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，由动脉壁上胆固醇斑块的积聚引起。 这些斑块是由巨噬细胞泡沫细胞积聚形成的，这是对氧化的炎症反应 受损内皮细胞的低密度脂蛋白(OxLDL)。游离脂肪酸受体4(FFAR4)，也称为 G蛋白偶联受体120(GPR120)是一种长链不饱和脂肪酸受体，表达于 脂肪细胞、内皮细胞和巨噬细胞。激活FFAR4有助于维持代谢动态平衡 调节脂肪生成、胰岛素敏感性和炎症。虽然FFAR4最出名的是它的保护作用 在预防肥胖和糖尿病方面，最近的研究表明，FFAR4可能也发挥着重要的作用 在预防动脉粥样硬化和心血管疾病中的作用。鉴于FAR4的S在抗炎信号和 在巨噬细胞中的高表达，我们设计了实验来验证FFAR4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。这些实验将需要 从野生型和FFAR4基因敲除小鼠中获得的巨噬细胞，在某些情况下，巨噬细胞 使用FFAR4激动剂。在目标1，我们将研究FFAR4缺乏对巨噬细胞泡沫细胞的影响 队形。具体来说，我们将确定FFAR4缺乏是否会增加oxLDL的摄取(目标1.1)， 减少胆固醇流出(目标1.2)，减少巨噬细胞迁移(目标1.3)。在目标2中，我们将 研究FFAR4用来防止泡沫细胞形成的信号机制，并测试 假设规范的Gaq/11 FFAR4信号通过以下方式减少胆固醇摄取并促进胆固醇外流 抑制转录因子PPARg。在目标3中，我们将研究FFAR4在脑内的生理作用。 动脉硬化。Aim 3.1将研究体内FFAR4缺乏对血脂水平和循环的影响 炎性细胞因子。AIM 3.2将评估动脉粥样硬化病变大小差异和免疫细胞激活 来自FFAR4+/+或FFAR4-/-小鼠的骨髓移植后LDLR-/-小鼠的主动脉状态。这个 这些拟议研究的结果将揭示FFAR4的生物学功能和 FFAR4如何防止巨噬细胞泡沫细胞的形成，这是动脉粥样硬化的标志。最终， 我们目前和未来的联合研究可能会将FFAR4确定为治疗动脉粥样硬化的新靶点。

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.