Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan; and Department of Biochemistry, Kyoto University Graduate School of Pharmaceutical Science, Sakyo, Kyoto, Japan.
Physiol Rev. 2020 Jan 1;100(1):171-210. doi: 10.1152/physrev.00041.2018. Epub 2019 Sep 5.
Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.
脂肪酸在生物反应中作为能量底物被代谢和合成。长链和中链脂肪酸主要来源于饮食中的甘油三酯，短链脂肪酸（SCFAs）则由肠道微生物发酵不可消化的膳食纤维产生，它们构成了代谢网络中游离脂肪酸（FFAs）的主要来源。最近，越来越多的证据表明，FFAs 不仅作为能量来源，还作为一组被称为游离脂肪酸受体（FFARs）的孤儿 G 蛋白偶联受体（GPCR）的天然配体，以多种方式将代谢和免疫相互交织在一起，例如通过炎症调节和肽激素的分泌。迄今为止，已经鉴定和表征了几种被不同链长的 FFAs 激活的 FFAR。特别是，FFAR1（GPR40）和 FFAR4（GPR120）被长链饱和和不饱和脂肪酸激活，而 FFAR3（GPR41）和 FFAR2（GPR43）被 SCFAs 激活，主要是乙酸盐、丁酸盐和丙酸盐。在这篇综述中，我们讨论了最近关于 FFAR 介导的信号转导通路在调节代谢和免疫反应中的关键生理功能的报告。我们还试图揭示开发代谢和免疫紊乱治疗方法的未来研究机会。
