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.
Highlights
The prevalence of gastroesophageal reflux disease (GERD) has been reported to be increasing
GW9508 caused mild relaxation in lower esophageal sphincter (LES) sling and clasp muscles at rest (24.0 ± 6.0 and 30.0 ± 6.3% of 1 × 10−6 M carbacholinduced tone, respectively; both n = 3), there was no significant difference compared with its vehicle (60% methanol)-induced relaxation (p > 0.05, 12.2 ± 1.6 and 18.0 ± 3.1% of 1 × 10−6 M carbachol-induced tone, respectively; n = 3 and 6)
The FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations, and the relative efficacy to cause relaxation was TUG891 > GSK137647 in both clasp and sling strips (Figure 2; n ≥ 4). This suggests that free fatty acid receptor 1 (FFA1) and FFA4 agonists can cause relaxation of the porcine LES
Summary
The prevalence of GERD has been reported to be increasing. Possible risk factors such as obesity, diabetes, smoking, alcohol, pregnancy, hiatal hernia, delayed stomach emptying, NSAIDs use, and sweet or fatty food are associated with GERD (Jarosz and Taraszewska, 2014; Asl et al, 2015). The sustained closure of LES can prevent esophagus from damage caused by gastric acid reflux. LES maintains tonic contraction modulated by myogenic, neural, and neurohumoral factors (Farré and Sifrim, 2008). The main underlying mechanism of GERD is LES incompetence that is caused by transient LES relaxations or decreased LES resting tone. Some drugs, food or cigarette smoking may decrease LES pressure (Bredenoord et al, 2005; Farré, 2013).
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