Long-Chain Fatty Acid Receptors Mediate Relaxation of the Porcine Lower Esophageal Sphincter

Abstract

Long-chain fatty acids activate the free fatty acid receptor 1 (FFA1) and FFA4. In the gastrointestinal system, FFA1 and FFA4 have been found in the pancreas and intestine. Fatty food and decreased lower esophageal sphincter (LES) motility are associated with gastroesophageal reflux disease. The effect of long-chain fatty acids on the esophageal motility is unknown. The purpose of this study is to investigate the effects of long-chain fatty acids on the porcine LES motility ex vivo using isometric transducers. In endothelin 1-precontracted porcine LES strips, the FFA1 selective agonists, fasiglifam, TUG424, and GW9508, caused marked relaxations in a concentration-dependent manner. The relative efficacies to elicit relaxation were GW9508 > TUG424 > fasiglifam in both clasp and sling strips. In contrast, the FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations. In addition, the endogenous FFA1 agonist DHA caused a mild relaxation whereas GW1100, an FFA1 antagonist, inhibited GW9508 induced relaxation of the porcine LES clasp and sling muscle. Both real-time PCR and immunohistochemistry revealed that FFA1 and FFA4 were expressed in the porcine LES. Real-time PCR analysis showed that the FFA4 expression was much lower than FFA1. Taken together, long-chain fatty acid receptor agonists elicit relaxation of the porcine LES. FFA1 might influence LES motility.

Expression of FFAR3 and FFAR4 Is Increased in Gastroesophageal Reflux Disease

“…Interestingly, no correlation was observed between the FFAR expression and patients’ perception of the symptoms, regardless of the disease subtype. The results we obtained correspond with the study of Tsai et al [ 24 ], showing that the selective agonists of FFAR1 (fasiglifam, TUG424) induce the relaxation of porcine LES strips ex vivo in a dose-dependent manner.…”

“…The results we obtained correspond with the study of Tsai et al [24], showing that the selective agonists of FFAR1 (fasiglifam, TUG424) induce the relaxation of porcine LES strips ex vivo in a dose-dependent manner. Interestingly, similarly to Tsai et al [24], we observed a low expression of FFAR4 in esophageal samples. In line with our observations, they found that FFAR4 agonists (GW9508 and GSK137647) were less potent in relaxing the LES than those of FFAR1.…”

“…Interestingly, similarly to Tsai et al [ 24 ], we observed a low expression of FFAR4 in esophageal samples. In line with our observations, they found that FFAR4 agonists (GW9508 and GSK137647) were less potent in relaxing the LES than those of FFAR1.…”