Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload

Abstract

Aims Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for endogenous medium/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. Methods and Results In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodeling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-days post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signaling and oxylipin synthesis as well as reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signaling-deficient Ffar4 R270H polymorphism correlated with eccentric remodeling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. Conclusions Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

Free fatty acid receptor 4 (FFAR4) regulates cardiac oxylipin balance to promote inflammation resolution in a model of heart failure preserved ejection fraction secondary to metabolic syndrome

“…Here, we also report the first data demonstrating that loss of Ffar4 reduced cardiac 18-HEPE levels in vivo, supporting our prior in vitro data from cardiac myocytes indicating that activation of Ffar4 increased 18-HEPE levels (33). Furthermore, loss of Ffar4 increased 12-HETE levels, increasing the 12-HETE/18-HEPE ratio, and suggesting a more pro-inflammatory state in the male Ffar4KO heart both at baseline and in response to the HFpEF-MetS diet.…”

“…In summary, the loss of Ffar4 in females resulted in greater obesity in response to the HFpEF-MetS diet, but this had no worsening effect on cardiac function as was observed in male Ffar4KO mice. This sexbased difference was similar to our prior report (33), and as such, we did not investigate the cardiac phenotype in females further.…”

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

“…GPR120 KO mice are unable to adapt to pressure overload induced by transverse aortic constriction [ 89 , 90 ]. GPR120 stimulates ABCA 1- ABCG 1 -mediated cholesterol efflux and is protective against atherosclerosis [ 91 ].…”

“…GPR120 stimulates ABCA 1- ABCG 1 -mediated cholesterol efflux and is protective against atherosclerosis [ 91 ]. In humans, GPR120 expression is decreased in heart failure [ 92 ], while the R270H polymorphism correlated with an eccentric remodeling in a large clinical cohort [ 90 ]. GPR120 agonists protect endothelial cells from oxLDL induced toxicity by decreasing E-selectin/VCAM 1 expression [ 93 ].…”

Does FFAR4 Agonism have Therapeutic Potential in Cardiometabolic Disease?

“…Their article ( 3 ) follows a recent publication which reports a cardioprotective role for FFAR4 in models of pressure overload and associations between the R270H polymorphism (affecting Ga/q signaling capacity) and eccentric remodeling in patient cohorts ( 5 ). Of note, this FFAR4 variant has previously been associated with an increased risk of obesity in European populations ( 6 ), though this association has not been consistently observed in different study populations ( 7 ) and the loss of FFAR4 expression or activity alone may not be sufficient to induce obesity.…”