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Review
. 2022 Nov 1;37(6):311-322.
doi: 10.1152/physiol.00007.2022. Epub 2022 Aug 9.

Signaling through Free Fatty Acid Receptor 4 Attenuates Cardiometabolic Disease

Timothy D O'Connell  1 , Katherine A Murphy  1 , Naixin Zhang  1 , Sara J Puccini  1 , Chastity L Healy  1 , Brian A Harsch  2 , Michael J Zhang  1 , Gregory C Shearer  2
Affiliations
Review

Signaling through Free Fatty Acid Receptor 4 Attenuates Cardiometabolic Disease

Timothy D O'Connell et al. Physiology (Bethesda). .

Abstract

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.

Keywords: 18-hydroxyeicosapentaenoic acid (18-HEPE); cardiometabolic disease; free fatty acid receptor 4 (Ffar4); heart; specialized proresolving mediators (SPM); ω3-polyunsaturated fatty acids (ω3-PUFAs).

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the author.

Figures

FIGURE 1.
FIGURE 1.
Free fatty acid receptor 4 (Ffar4) mediates a G-protein receptor (GPR)-signaling amplification cascade in cardiac myocytes and macrophages A: Ffar4 is expressed in cardiac myocytes and macrophages. ChemR23 (RvE1) and GPR31 (12-HETE) are expressed in macrophages, and expression is postulated in cardiac myocytes (gray text). Ffar4 ligands include high-efficacy polyunsaturated fatty acid (PUFAs; solid line, ω3-PUFAs: green; ω6-PUFAs: purple), and low-efficacy saturated fatty acid (SFAs; dashed line). In cardiac myocytes, Ffar4 induces synthesis of 18-HEPE and potentially RvE1 (gray text), which is cytoprotective. In cardiometabolic disease, Ffar4 increases cardiac 18-HEPE level and decreases 12-HETE levels, which we hypothesize is cardioprotective. In macrophages, Ffar4 and ChemR23 induce an M2-like proresolving phenotype, whereas GPR31 induces an M1-like proinflammatory phenotype. Finally, we postulate cellular cross talk between myocytes and macrophages based on cell-specific oxylipin production might be achieved through oxylipin export to HDL and subsequent release through binding to HDL receptor scavenger receptor B1 (SR-B1) and local release. SA, stearic acid; PA, palmitic acid. B: in cardiac myocytes, Ffar4 signals through either Gq- and β-Arr2 to activate cytosolic phospholipase A2α (cPLA2α). cPLA2α cleaves PUFAs from the Sn2 position in membrane phospholipids at the outer nuclear membrane [eicosapentaenoic acid (EPA): green; arachidonic acid (AA): purple; or other PUFAs: gray]. Released PUFAs are further oxidatively metabolized by lipoxygenases (LOX), cyclooxygenases (COX), and CYPhydrolases/CYPepoxygenases (CYP). EPA is metabolized by COX or CYP enzymes to 18-HEPE (red), whereas AA is metabolized by 12-lipoxygenase to make 12-HETE (blue), which again is inhibited by Ffar4 in the context of cardiometabolic disease. Oxylipins have 4 fates: 1) remain free in the cell (nonesterified); 2) be reesterified into the membrane (sequestration); 3) be exported as a free oxylipin, a low-frequency event; or 4) be exported into HDL.
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