Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Endocrinology. 2021 Aug 1;162(8). doi: 10.1210/endocr/bqab111.
Free fatty acids (FFAs) are implicated in the pathogenesis of metabolic diseases that includes obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD). FFAs serve as ligands for free fatty acid receptors (FFARs) that belong to the family of rhodopsin-like G protein-coupled receptors (GPCRs) and are expressed throughout the body to maintain energy homeostasis under changing nutritional conditions. Free fatty acid receptor 4 (FFAR4), also known as G protein-coupled receptor 120, is a long-chain fatty acid receptor highly expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. Furthermore, dysfunction of FFAR4 is associated with insulin resistance, obesity, and eccentric remodeling in both humans and mice, making FFAR4 an attractive therapeutic target for treating or preventing metabolic diseases. While much of the previous literature on FFAR4 has focused on its role in obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the development of atherosclerosis and CVD. Most notably, FFAR4 activation reduces monocyte-endothelial cell interaction, enhances cholesterol efflux from macrophages, reduces lesion size in atherogenic mouse models, and stimulates oxylipin production in myocytes that functions in a feed-forward cardioprotective mechanism. This review will focus on the role of FFAR4 in metabolic diseases and highlights an underappreciated role of FFAR4 in the development of atherosclerosis and CVD.
游离脂肪酸（FFAs）与代谢疾病的发病机制有关，这些疾病包括肥胖、2 型糖尿病和心血管疾病（CVD）。FFAs 作为游离脂肪酸受体（FFARs）的配体，FFARs 属于视紫红质样 G 蛋白偶联受体（GPCR）家族，在体内表达广泛，以在不断变化的营养条件下维持能量稳态。游离脂肪酸受体 4（FFAR4），也称为 G 蛋白偶联受体 120，是一种长链脂肪酸受体，在脂肪细胞、内皮细胞和巨噬细胞中高度表达。FFAR4 的激活有助于通过调节脂肪生成、胰岛素敏感性和炎症来维持代谢稳态。此外，FFAR4 的功能障碍与人类和小鼠的胰岛素抵抗、肥胖和离心性重构有关，这使得 FFAR4 成为治疗或预防代谢性疾病的有吸引力的治疗靶点。尽管之前关于 FFAR4 的大部分文献都集中在其在肥胖和糖尿病中的作用，但最近的研究表明，FFAR4 也可能在动脉粥样硬化和 CVD 的发展中发挥重要作用。值得注意的是，FFAR4 的激活可减少单核细胞-内皮细胞相互作用，增强巨噬细胞中的胆固醇流出，减少动脉粥样硬化小鼠模型中的病变大小，并刺激心肌细胞中的氧化脂素产生，从而发挥一种正向的心脏保护机制。这篇综述将重点介绍 FFAR4 在代谢性疾病中的作用，并强调 FFAR4 在动脉粥样硬化和 CVD 发展中的作用被低估。
