Free Fatty Acid Receptors in Health and Disease

Abstract

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.

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty

“…This evidence indicates that a higher-fiber diet and, indirectly, increasing SCFA may be a promising intervention strategy for counteracting age-related physical impairment. Similarly, only a small number of pre-clinical studies confirm the neuroprotective effects of SCFA, MCFA, and high-fiber diets in cognitive frailty, as we and Kimura et al (141) recently reviewed in depth elsewhere (138,141).…”

Starvation causes female-to-male sex reversal through lipid metabolism in the teleost fish, medaka (Olyzias latipes)

“…Polyunsaturated fatty acids are involved in gene expression via nuclear receptor families (Bordoni et al, 2006;Salter and Tarling, 2007). In addition, dietary short-and medium-chain saturated fatty acids are known as both signaling factors and energy sources (Schönfeld and Wojtczak, 2016; Kimura et al, 2019). Interestingly, 13% of FAS inhibitor (C75)-treated females showed sex reversal despite their dietary lipid intake (e.g.…”

Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein

“…LA itself is detected by FFA receptor GPR40/FFAR1 (31). GPR40-mediated FFA signaling is a powerful mediator of 9 inflammation in human tissues and in animal models (32). Regarding the potential impact of LA pathway remodeling on fluidity and elasticity of biological membranes, we note that the FFA composition of phospholipid bilayers is a key element in maintaining surface tension in lungs, and alteration of LA pathway lipid composition is observed in acute respiratory distress syndrome and severe pneumonia (33), both of which are key symptoms of SARS-CoV-2 5 infection.…”