Dataset Information

Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells.

ABSTRACT:

Objectives

The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G_?q-coupled free fatty acid receptors FFA1 and G_?s-coupled bile acid receptors GPBAR1.

Methods

Experiments were performed using ileal organoids generated from mice transgenically expressing fluorescent reporters (Epac2-camps and GCaMP3) under control of the proglucagon promoter. Electrophysiology and single cell imaging were performed on identified L-cells in organoids, and GLP-1 secretion from cultured organoids was measured by immunoassay.

Results

The FFA1 ligand TAK-875 triggered L-cell electrical activity, increased intracellular calcium, and activated a depolarizing current that was blocked by the TRPC3 inhibitor Pyr3. TAK-875 triggered GLP-1 secretion was Pyr3 sensitive, suggesting that the TRPC3 channel links FFA1 activation to calcium elevation and GLP-1 release in L-cells. GPBAR1 agonist triggered PKA-dependent L-type Ca²⁺ current activation and action potential firing in L-cells. The combination of TAK-875 and a GPBAR1 agonist triggered synergistic calcium elevation and GLP-1 secretory responses.

Conclusions

FFA1 and GPBAR1 activation individually increased electrical activity in L-cells by recruiting pathways that include activation of TRPC3 and L-type voltage-gated Ca²⁺ channels. Synergy between the pathways activated downstream of these receptors was observed both at the level of Ca²⁺ elevation and GLP-1 secretion.

SUBMITTER: Goldspink DA

PROVIDER: S-EPMC5784317 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells.

Goldspink Deborah A DA Lu Van B VB Billing Lawrence J LJ Larraufie Pierre P Tolhurst Gwen G Gribble Fiona M FM Reimann Frank F

Molecular metabolism 20171111

<h4>Objectives</h4>The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G<sub>αq</sub>-coupled free fatty acid receptors FFA1 and G<sub>αs</sub>-coupled bile acid receptors GPBAR1.<h4>Methods</h4>Experiments were performed using ileal organoids generated from mice transgenically expressing f ...[more]

PMID: 29167062

Similar Datasets

Project description:BackgroundLiver damage from nonalcoholic steatohepatitis (NASH) presents a significant challenge to the health and productivity of ruminants. However, the regulatory mechanisms behind variations in NASH susceptibility remain unclear. The gut‒liver axis, particularly the enterohepatic circulation of bile acids (BAs), plays a crucial role in regulating the liver diseases. Since the ileum is the primary site for BAs reabsorption and return to the liver, we analysed the ileal metagenome and metabolome, liver and serum metabolome, and liver single-nuclei transcriptome of NASH-resistant and susceptible goats together with a mice validation model to explore how ileal microbial BAs metabolism affects liver metabolism and immunity, uncovering the key mechanisms behind varied NASH pathogenesis in dairy goats.ResultsIn NASH goats, increased total cholesterol (TC), triglyceride (TG), and primary BAs and decreased secondary BAs in the liver and serum promoted hepatic fat accumulation. Increased ileal Escherichia coli, Erysipelotrichaceae bacterium and Streptococcus pneumoniae as well as proinflammatory compounds damaged ileal histological morphology, and increased ileal permeability contributes to liver inflammation. In NASH-tolerance (NASH-T) goats, increased ursodeoxycholic acid (UDCA), isodeoxycholic acid (isoDCA) and isolithocholic acid (isoLCA) in the liver, serum and ileal contents were attributed to ileal secondary BAs-producing bacteria (Clostridium, Bifidobacterium and Lactobacillus) and key microbial genes encoding enzymes. Meanwhile, decreased T-helper 17 (TH17) cells and increased regulatory T (Treg) cells proportion were identified in both liver and ileum of NASH-T goats. To further validate whether these key BAs affected the progression of NASH by regulating the proliferation of TH17 and Treg cells, the oral administration of bacterial UDCA, isoDCA and isoLCA to a high-fat diet-induced NASH mouse model confirmed the amelioration of NASH through the TH17 cell differentiation/IL-17 signalling/PPAR signalling pathway by these bacterial secondary BAs.ConclusionThis study revealed the roles of ileal microbiome and its secondary BAs in resilience and susceptibility to NASH by affecting the hepatic Treg and TH17 cells proportion in dairy goats. Bacterial UDCA, isoDCA and isoLCA were demonstrated to alleviate NASH and could be novel postbiotics to modulate and improve the liver health in ruminants. Video Abstract.

Dataset Information

Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells.

Objectives

Methods

Results

Conclusions

Publications

Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells.

Similar Datasets

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