ABSTRACT
SCOPE: The secretion of gut hormones, such as cholecystokinin (CCK) is stimulated by fatty acids. Although a chain length-dependent mechanism has been proposed, other structural relationships to releasing activity remain unclear. We aimed to elucidate specific structures in fatty acids that are responsible for their CCK-releasing activity, and related sensing mechanisms in enteroendocrine cells. METHODS AND RESULTS: CCK secretory activities were examined in a murine CCK-producing cell line STC-1 by exposing the cells to various modified fatty acids produced by gut lactic acid bacteria. The effects of fatty acids on gastric emptying rate as a CCK-mediated function were examined using acetaminophen and phenol red methods in rats. Out of more than 30 octadecanoic-derived fatty acids tested, 5 oxo-fatty acids potently stimulated CCK secretion without cytotoxic effects in STC-1 cells. Three fatty acids had a distinct specific structure containing one double bond, whereas the other two had two double bonds, nearby an oxo residue. CCK secretion induced by representative fatty acids (10-oxo-trans-11-18:1 and 13-oxo-cis-9,cis-15-18:2) was attenuated by a fatty acid receptor G-protein coupled receptor 40 antagonist. Oral administration of 13-oxo-cis-9,cis-15-18:2 lowered the gastric emptying rate in rats in a dose- and structure-dependent manner. CONCLUSION: These results reveal a novel fatty acid-sensing mechanism in enteroendocrine cells.
Subject(s)
Cholecystokinin/metabolism , Enteroendocrine Cells/metabolism , Fatty Acids/pharmacology , Receptors, G-Protein-Coupled/metabolism , Acetaminophen/pharmacokinetics , Administration, Oral , Animals , Cell Line , Dose-Response Relationship, Drug , Enteroendocrine Cells/drug effects , Fatty Acids/administration & dosage , Fatty Acids/chemistry , Gastric Emptying/drug effects , Gastrointestinal Microbiome/physiology , Male , Mice , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/antagonists & inhibitorsABSTRACT
We recently demonstrated that a diunsaturated aldehyde, trans,trans-2,4-decadienal (2,4-decadienal), potently stimulated secretion of cholecystokinin in the enteroendocrine cell line. Gut hormones such as cholecystokinin and serotonin play critical roles in reducing postprandial gastric emptying. In the present study, we first demonstrated that oral administration of 2,4-decadienal (50-100 mg/kg) reduced gastric emptying rate in rats, assessed by both the acetaminophen absorption test and the phenol red recovery method. In contrast, saturated aldehyde, alcohol, and fatty acids having the same chain length as 2,4-decadienal did not affect the gastric emptying rate. Duodenal administration of 2,4-decadienal potently reduced gastric emptying rate, but intraperitoneal administration did not. Furthermore, the gastric inhibitory effect of 2,4-decadienal was attenuated by treatment with a serotonin receptor antagonist. These results demonstrated that 2,4-decadienal in the small intestinal lumen has a potent inhibitory effect on gastric emptying, possibly through stimulation of the serotonin-producing enteroendocrine cells.
Subject(s)
Aldehydes/pharmacology , Gastric Emptying/drug effects , Intestines/drug effects , Serotonin/physiology , Signal Transduction/drug effects , Acetaminophen/blood , Aldehydes/administration & dosage , Animals , Duodenum/drug effects , Enteroendocrine Cells/drug effects , Intestines/physiology , Male , Peritoneum/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
SCOPE: Cholecystokinin (CCK) producing cells sense luminal contents to regulate the exocrine pancreas, gastric motility, and appetite. Although long-chain fatty acids (FAs, ≥ C12) are well known to stimulate CCK secretion, the CCK-releasing activities of other aliphatic compounds, such as aldehydes (Alds) or alcohols (Alcs), have not been studied. METHODS AND RESULTS: We tested the CCK-releasing activities of various aliphatic compounds with various carbon chain lengths (C3-C13) and degrees of unsaturation in the enteroendocrine cell line STC-1. CCK released from the cell was measured using an ELISA, and intracellular calcium concentration was measured using Fura-2. Mono- and di-unsaturated Alds at 100 µM, but not saturated Alds, induced CCK secretion in STC-1 cells. Alcs and FAs failed to induce CCK secretion, regardless of carbon chain length or degree of unsaturation. Unsaturated Alds increased intracellular calcium concentration, but saturated Alds, Alcs, and FAs did not. Intracellular calcium mobilization and CCK secretion induced by unsaturated Alds was abolished in the absence of extracellular calcium. In addition, the inhibition of the transient receptor potential ankyrin 1 (TRPA1) channel suppressed unsaturated Ald-induced CCK secretion and intracellular calcium mobilization. CONCLUSION: Unsaturated Alds are potent aliphatic stimulants for CCK secretion through the activation of TRPA1.
