Dataset Information

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate.

ABSTRACT:

Background

Propionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein-coupled receptors (GPCRs) are expressed by enteroendocrine L cells that contain anorectic peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal responses utilizing selective ligands including an FFA3 antagonist, in mouse and human colonic mucosa.

Methods

Vectorial ion transport was measured in native colonic preparations from normal mouse and human colon with intact submucosal innervation. Endogenous fecal pellet propulsion was monitored in colons isolated from wild-type (WT) and PYY-/- mice.

Key results

FFA2 and FFA3 signaling differed significantly. FFA2 agonism involved endogenous L cell-derived PYY and was glucose dependent, while FFA3 agonism was independent of PYY and glucose, but required submucosal enteric neurons for activity. Tonic FFA3 activity was observed in mouse and human colon mucosa. Apical propionate responses were a combination of FFA2-PYY mediation and FFA3 neuronal GLP-1- and CGRP-dependent signaling in mouse ascending colon mucosa. Propionate also slowed WT and PYY-/- colonic transit, and this effect was blocked by a GLP-1 receptor antagonist.

Conclusions & inferences

We conclude that luminal propionate costimulates FFA2 and FFA3 pathways, reducing anion secretion and slowing colonic motility; FFA2 via PYY mediation and FFA3 signaling by activation of enteric sensory neurons.

SUBMITTER: Tough IR

PROVIDER: S-EPMC6282569 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate.

Tough Iain R IR Forbes Sarah S Cox Helen M HM

Neurogastroenterology and motility 20180823 12

<h4>Background</h4>Propionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein-coupled receptors (GPCRs) are expressed by enteroendocrine L cells that contain anorectic peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal ...[more]

PMID: 30136343

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Project description:AIMS:Signalling through the Wnt pathway is integrally associated with colon carcinogenesis. Although activating mutations in the genes for adenomatous polyposis coli (APC) and beta-catenin are clearly associated with colon cancer, less is understood about the role of the upstream secreted ligands (Wnts) and their receptors (frizzled, Fz) in this process. In other systems, increased Wnt signalling has been shown to alter the expression of components of this pathway. This study was designed to test the hypothesis that colon cancer is characterised by aberrant expression of specific Wnt genes and Fz receptors. METHODS:The expression of Wnt genes was assessed by in situ, antisense RNA hybridisation in paraffin wax embedded samples of normal and malignant human colon tissues with probes specific for the individual Wnt genes. The expression of Fz1 and Fz2 was determined by immunoperoxidase based antibody staining on human tissues. RESULTS:Changes in the expression of some ligands and receptors were seen in colon cancer. For example, Wnt2 mRNA was detected in colon cancer but was undetectable in normal colonic mucosa. Differential expression of Wnt5a in normal mucosa was also noted, with increased expression at the base of the crypts compared with the luminal villi and slightly increased expression in colon cancer. Wnt7a exhibited minimal expression in both normal and malignant colon tissues, whereas other Wnt ligands including Wnts 1, 4, 5b, 6, 7b, and 10b were expressed equally and strongly in both normal and malignant colon tissues. In defining cellular responses and phenotype, the type and distribution of Fz receptors may be as important as the pattern of Wnt ligand expression. No expression of Fz receptor 1 and 2 was seen in normal colonic mucosa and in well differentiated tumours. However, poorly differentiated tumours exhibited a high degree of Fz receptor expression, especially at the margin of cellular invasion. CONCLUSIONS:These data indicate that the expression of members of the Wnt signal transduction pathway, distinct from APC and beta-catenin, is integrally associated with the process of colon carcinogenesis. Wnt2, and possibly Wnt5a, may be involved in the progression from normal mucosa to cancer and the expression of Fz1/2 receptors may be involved in processes associated with tumour invasion. Altered expression of these Wnts and Fz receptors may prove useful as prognostic or diagnostic markers for patients with colon cancer.

Dataset Information

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate.

Background

Methods

Key results

Conclusions & inferences

Publications

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate.

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