scholarly journals Multiple ligand recognition sites in free fatty acid receptor 2 (FFA2R) direct distinct neutrophil activation patterns

2021 ◽  
pp. 114762
Author(s):  
Simon Lind ◽  
André Holdfeldt ◽  
Jonas Mårtensson ◽  
Kenneth L. Granberg ◽  
Huamei Forsman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Neutrophil Activation ◽  
Ligand Recognition ◽  
Activation Patterns ◽  
Acid Receptor ◽  
Recognition Sites ◽  
Free Fatty Acid Receptor ◽  
Multiple Ligand ◽  
Fatty Acid Receptor

scholarly journals Multiple ligand recognition sites in free fatty acid receptor 2 (FFAR2) direct distinct neutrophil activation patterns

2020 ◽  
Author(s):  
Simon Lind ◽  
André Holdfeldt ◽  
Jonas Mårtensson ◽  
Kenneth L. Granberg ◽  
Huamei Forsman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Nadph Oxidase ◽  
Neutrophil Activation ◽  
Allosteric Modulators ◽  
Activation Patterns ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
Sensitizing Effect ◽  
Fatty Acid Receptor

AbstractNon-activating positive allosteric modulators specific for free fatty acid receptor 2 (FFAR2) increased the activity induced by orthosteric agonists to trigger a rise in intracellular Ca2+ ([Ca2+]i) and activate the O2− producing neutrophil NADPH-oxidase. In addition, two allosteric modulators (Cmp58 and AZ1729) recognized by different receptor domains on FFAR2, cooperatively triggered activation without any rise in [Ca2+]i. To gain insights into FFAR2 modulation and signaling, we set out to identify structurally diverse allosteric FFAR2 modulators. Initially, we identified two molecules that directly activate neutrophils and these were classified as an allosteric FFAR2 agonists and an orthosteric agonist, respectively. Based on the sensitizing effect on the neutrophil response to propionate, ten non-direct-activating molecules were classified as allosteric FFAR2 modulators. One of these synergistically activated neutrophils when combined with AZ1729, but not when combined with Cmp58. The remaining nine compounds synergistically induced the same type of biased neutrophil signaling but only when combined with Cmp58. The activation signals down-stream of FFAR2 when stimulated by two allosteric modulators with different binding sites were in most cases biased in that two complementary modulators together triggered an activation of the NADPH-oxidase, but no increase in [Ca2+]i. The neutrophil activation pattern achieved when two functionally “AZ1729- or “Cmp58-like” allosteric FFAR2 modulators were combined, supporting a model for activation in which FFAR2 has two different sites that selectively bind allosteric modulators. The novel neutrophil activation patterns and receptor down-stream signaling mediated by two cross-sensitizing allosteric modulators represent a new regulatory mechanism that controls FFAR2 receptor function.

Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus

Hippocampus ◽  
2008 ◽  
Vol 18 (3) ◽  
pp. 326-333 ◽  
Author(s):  
Dexuan Ma ◽  
Li Lu ◽  
Nadezhda B. Boneva ◽  
Shogo Warashina ◽  
Desislav B. Kaplamadzhiev ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Acid Receptor ◽  
Neurogenic Niche ◽  
Free Fatty Acid Receptor ◽  
Fatty Acid Receptor

scholarly journals Regulation of Free Fatty Acid Receptor 4 on Inflammatory Gene Induced by LPS in Large Yellow Croaker (Larimichthys crocea)

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengjiao Wu ◽  
Qingfei Li ◽  
Kangsen Mai ◽  
Qinghui Ai
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Mrna Expression ◽  
Head Kidney ◽  
Large Yellow Croaker ◽  
Larimichthys Crocea ◽  
Inflammatory Genes ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
Fatty Acid Receptor

Free fatty acid receptor 4 (FFAR4) plays a key role in regulating the inflammatory response in mammals. The present study aimed to investigate the function of large yellow croaker FFAR4 on inflammation. In the present study, ffar4 was widely expressed in 10 tissues of large yellow croaker including gill, head kidney and spleen. Further studies showed that treatment of head kidney macrophages with agonists (TUG891 or GSK137647A) or overexpression of ffar4 reduced the mRNA expression of pro-inflammatory genes induced by LPS, and increased the expression of pparγ. Treatment of macrophages with antagonist AH7614 increased the mRNA expression of pro-inflammatory genes induced by LPS, and decreased the mRNA expression of pparγ. In order to verify the immunomodulatory effect of PPARγ, PPARγ was overexpressed in macrophages which significantly reduced the mRNA expression of pro-inflammatory genes il6, il1β, il8, tnfα and cox2. Moreover, results of dual-luciferase assays showed that PPARγ downregulated the transcriptional activity of il6 and il1β promoters. In conclusion, FFAR4 showed anti-inflammatory effects on LPS-induced inflammation in large yellow croaker.

scholarly journals Free fatty acid receptor 4 is a nutrient sensor that resolves inflammation to maintain cardiac homeostasis

2019 ◽  
Author(s):  
Katherine A. Murphy ◽  
Brian A. Harsch ◽  
Chastity L. Healy ◽  
Sonal S. Joshi ◽  
Shue Huang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Cardiac Myocytes ◽  
Transcriptome Analysis ◽  
Pressure Overload ◽  
Plasma Lipoproteins ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
Anti Inflammatory ◽  
Fatty Acid Receptor

AbstractBackgroundNon-­resolving activation of immune responses is central to the pathogenesis of heart failure (HF). Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor (GPR) for medium-and long-chain fatty acids (FA) that regulates metabolism and attenuates inflammation in diabetes and obesity. Here, we tested the hypothesis that Ffar4 functions as a cardioprotective nutrient sensor that resolves inflammation to maintain cardiac homeostasis.MethodsMice with systemic deletion of Ffar4 (Ffar4KO) were subjected to pressure overload by transverse aortic constriction (TAC). Transcriptome analysis of cardiac myocytes was performed three days post-TAC. Additionally, Ffar4-mediated effects on inflammatory oxylipin production in cardiac myocytes and oxylipin composition in plasma lipoproteins were evaluated.ResultsIn Ffar4KO mice, TAC induced more severe remodeling, identifying an entirely novel cardioprotective role for Ffar4 in the heart. Transcriptome analysis 3-days post-TAC indicated a failure to induce cell death and inflammatory genes in Ffar4KO cardiac myocytes, as well as a specific failure to induce cytoplasmic phospholipase A2α (cPLA2α) signaling genes. In cardiac myocytes, Ffar4 signaling through cPLA2α-cytochrome p450 ω/ω-1 hydroxylase induced production of the EPA-derived anti-inflammatory oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Systemically, loss of Ffar4 altered oxylipin content in circulating plasma lipoproteins consistent with a loss of anti-inflammatory oxylipins at baseline, and inability to produce both pro-inflammatory and pro-resolving oxylipins following TAC. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in HF.ConclusionsOur results identify a novel function for Ffar4 in the heart as a FA nutrient sensor that resolves inflammation to maintain cardiac homeostasis.

Distribution and regulation of protein expression of the free fatty acid receptor GPR120

2009 ◽  
Vol 379 (4) ◽  
pp. 427-434 ◽  
Author(s):  
Satoshi Miyauchi ◽  
Akira Hirasawa ◽  
Tomoyo Iga ◽  
Ning Liu ◽  
Chisato Itsubo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Protein Expression ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
Fatty Acid Receptor
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