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Roles of Short-Chain Fatty Acids and Their Receptors in Colonic Motility

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Roles of Short-Chain Fatty Acids and Their Receptors in Colonic Motility Review Bioscience Microflora Vol. 29 (1), 31–40, 2010 Roles of Short-Chain Fatty Acids and their Receptors in Colonic Motility Shin-ichiro KARAKI1 and Atsukazu KUWAHARA1* 1Laboratory of Physiology, Institute for Environmental Sciences, University of Shizuoka, 52–1 Yada, Suruga-Ku, Shizuoka 422-8526, Japan Received for Publication, October 29, 2009 Short chain fatty acids (SCFAs) are major anions in the large intestine. They are produced by bacterial fermentation of dietary fiber. However, the mechanism by which intraluminal SCFAs are sensed is unknown. Free fatty acids including SCFAs have recently been demonstrated to act as ligands for several G-protein-coupled receptors (GPCRs: FFA1, FFA2, FFA3, GPR84, GPR109A and GPR120). SCFAs are ligands for FFA2 and FFA3. These receptors are proposed to play a variety of physiological and pathophysiological roles in the intestine. In rat and human colons, FFA2 and/or FFA3 are located in mucosal enteroendocrine cells containing peptide YY (PYY) and are related to energy balance. Among SCFAs, propionate and butyrate induce concentration-dependent phasic and tonic contractions in rat colonic circular muscle. These responses are not observed in mucosal free preparations. Thus, FFA2 and FFA3 are important molecular devices for monitoring the chemical composition in the colonic lumen. For the local function of SCFAs, it should be stressed that individual SCFAs have different modes of action on colonic smooth muscles. These different actions may be due to the relative contributions of FFA2 and FFA3 to the control of intestinal muscle activity. FFA2 and FFA3 may also contribute to the whole body energy balance through the release of gastrointestinal hormones related to feeding and satiety control. This review summarizes recent findings about the roles of deorphanized FFA receptors, especially, FFA2 and FFA3 and their contributions to the regulation of colonic motility. Key words: G-protein coupled receptor; short-chain fatty acid; FFA2; FFA3; human colon; colonic motility INTRODUCTION 43), transepithelial chloride secretion (26, 67), Short chain fatty acids (SCFAs) are 2–6 carbon colonocyte proliferation (48, 51), and to prevent monocarboxylates which are a subgroup of fatty acids. colorectal cancer (13). As a remote effect, infusion of They include acetate (C2), propionate (C3) and n- SCFAs into the colon (47) or ileum (10, 11) have also butyrate (C4), all of which are predominantly found in the been reported to inhibit proximal intestinal motility large intestine (62). They are produced by bacterial which is variously known as the “colonic brake”, “ileal fermentation of undigested carbohydrates from ingested brake” or “ileocolonic brake”. With respect to intestinal dietary fiber. SCFAs are major anions, present at about motility, SCFAs-induced colonic motility is reported to 100 mM in the lumen of the non-ruminant mammalian disappear in mucosal free preparations (38). Therefore, large intestine. Molar ratios of SCFAs in human fecal the effects of SCFAs in the intestinal lumen are content are reported as 50–60 mM acetate, 15–20 mM considered to be induced via activation of specific propionate, 10–20 mM butyrate (12). Luminal SCFAs receptors and/or via absorption by epithelial cells, but the are not only absorbed as nutrients by the intestinal mechanisms by which intraluminal SCFAs are sensed are epithelia but also influence various physiological and not known. pathophysiological actions in the intestine as chemical Recently, many G protein-coupled receptors (GPCRs) stimuli. For example, SCFAs have been reported to have been deorphanized. Among them, free fatty acid stimulate smooth muscle contractions (19, 38, 39, 42, (FFA) receptors have been identified as membrane receptors and play significant roles in nutritional regulation. Individual FFA receptors are expressed *Corresponding author. Mailing address: Laboratory of Physiology, Institute for Environmental Sciences, University of Shizuoka, 52–1 differentially, and they may play different functional Yada, Suruga-ku, Shizuoka 422-8526, Japan. roles. This finding has prompted re-evaluation of the Phone: +81-54-264-5707. FAX: +81-54-264-5707. mechanisms of actions of FFAs in health and disease. E-mail: [email protected] FFA1 (originally termed GPR40) and GPR120 are The review was presented at the Function of Intestinal Microbiota and activated by medium- and long-chain FFAs, whereas Food(FIMF) Joint Forum 2008, Tokyo, 2008. FFA2 (previously designated GPR43) and FFA3 31 32 S. KARAKI and A. KUWAHARA Table 1. Free fatty acid receptors Nomenclatures Other Names G-proteins Effectors Agonists Major expression cells Medium ~ Long-chain fatty acids Pancreatic cells, FFA1 GPR40 G Ca2+ q/11 (C12 ~ C18) Thiazolidinedione Enteroendocrine K cells cAMP SCFAs (C2 ~ C7) Immune cells, FFA2 GPR43 G G i/o q Ca2+ acetate = propionate = butyrate Enteroendocrine L cells SCFAs (C2 ~ C7) Adipocytes, FFA3 GPR41 G cAMP i/o propionate = butyrate > acetate Enteroendocrine L cells Enteroendocrine cells GPR120 G Ca2+ Long-chain fatty acids (C14 ~) q/11 in the colon Medium-chain fatty acids GPR84 G cAMP Immune cells i/o (C9 ~ C14) HM74A, cAMP Adipocytes, macrophages GPR109A G SCFAs (C4 ~ C8) Nicotinate PUMA-G i/o Ca2+ Intestinal epithelial cells (previously designated GPR41) are activated by SCFAs revealed high expression in insulin-producing pancreatic (56). In this review, we summarize recent findings about islets (2, 27). FFA1 was found to be enriched 2- to 100- the roles of deorphanized FFA receptors, especially, fold in pancreatic islets as compared to the whole FFA2 and FFA3 and their contributions to the regulation pancreas (4, 46). These results suggest that FFA1 acts as of colonic motility. a receptor for fatty acid-induced insulin secretion. As well as -cells, FFA1 is also reported to be present in - FREE FATTY ACID RECEPTORS cells (18). Moreover, FFA1 expression has been detected FFAs are known to possess a wide range of in various pancreas-derived cell lines, including MIN6, physiological effects through cellular metabolism and -TC-3, HIT-T15 and INS-1E (4, 27, 30, 52). FFA1 cell surface receptors. expression has also been detected in human and rat islets The genes encoding FFA1, FFA2 and FFA3, originally (17, 49, 60). Outside of the pancreas, the presence of termed GPR40, GPR43 and GPR41, respectively, have FFA1 mRNA has been reported in the small and large been identified as tandemly encoded genes present on intestines (4, 14, 27) and in the STC-1 cells. Expression human chromosome 19q13 (50). FFA1 receptor of FFA1 was demonstrated in the enteroendocrine cells of remained classified as an orphan until 2003. In 2003, the stomach and small intestine which contain a variety of three groups independently reported that the FFA1 was an gut hormones including glucagon-like peptide-1 (GLP-1) endogenous ligand for medium- and long-chain saturated and glucose-dependent insulinotropic polypeptide (GIP), and unsaturated fatty acids (4, 27, 30). Medium- and which both increase insulin secretion(14). Instead of long-chain FFAs also activate GPR84 and GPR120 (24, incretin hormones, in the pylorus and duodenum, FFA1 60). On the other hand, SCFAs activate FFA2 (GPR43) expression colocalized with gastrin, ghrelin, and FFA3 (GPR41) (5, 32, 41). FFA1, FFA2, and FFA3 cholecystokinin (CCK), peptide YY (PYY), secretin, represent a family of receptors because they are more serotonin and substance P expression (14). Outside the closely related to each other than any other known GI tract, FFA1 has been detected in the brain, immune GPCRs. Despite this, the family exhibits somewhat cells, MCF-7 human breast cell line and MDA-MB-231 limited similarity, 43% between FFA2 and FFA3, and 33 breast cancer cells (22, 23, 35, 36, 52, 68). and 34% for FFA1 compared aganist FFA2 and FFA3, Another medium- and long-chain fatty acids receptor, respectively (6). The receptors have been given a variety GPR120, is highly expressed in the human and mouse of names in the literature and these are summarized in intestinal tract and mouse enteroendocrine STC-1 cells Table 1. (24). GPR120 is expressed in GLP-1-containing intestinal L and K cells (24, 40). GPR84 is also a Tissue distribution free fatty acid receptor 1 (FFA1) medium-chain FFAs receptor. GPR84 is stimulated by All three initial reports on FFA1 (GPR40) showed high medium-chain FFA with carbon chain lengths of 9–14 levels of receptor mRNA in the pancreas (4, 27, 30). (63). GPR84 is not activated by short-chain and long- Expression analysis of FFA1 using RT-PCR, chain saturated and unsaturated FFAs, which do activate immunohistochemistry, and in situ hybridization FFA1, FFA2, FFA3 and GPR120 (63). Human GPR84 is ROLES OF SHORT-CHAIN FATTY ACIDS AND THEIR RECEPTORS IN COLONIC MOTILITY 33 expressed in the brain, heart, muscle, colon, thymus, knockout mice, release of GLP-1 and GIP was spleen, kidney, liver, intestine, placenta, lung and significantly reduced in response to a high-fat diet (14). leukocytes (64). GPR109A (also termed HM74A in These results suggest that incretin secretion might be humans and PUMA-G in mice), a nicotinic acid (niacin, impaired in FFA1 knockout mice and indicate a role for vitamin B3) receptor, has been reported to be activated by FFA1 in the secretion of these hormones. Another C4 - C8 fatty acids (57), and is expressed in adipocytes, GPCR, GPR120, is also activated by medium- to long- activated macrophages (61), and the apical membrane of chain fatty acids and induces GLP-1 secretion in mouse intestinal epithelial cells (59). enteroendocrine STC-1 cells. (24). Oral administration of FFA and direct administration to the colon also Physiological roles of FFA1 increase circulating GLP-1 and insulin levels in mice FFA1 is activated by more than 40 different medium- (24). Both FFA1 and GPR120 are activated in a smimlar and long-chain fatty acids with micromolar range manner by FFAs but FFA1 directly and GPR120 potency, and of these eicosatrienoic acid (C20:3) was the indirectly promote glucose-stimulated insulin secretion most potent with a pEC of 5.71 ± 0.11 (4).
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