Cloning, Identification and Functional Characterization of Bovine Free Fatty Acid Receptor-1 (FFAR1/GPR40) in Neutrophils

Manosalva, Carolina; Huertas, Jaqueline Mena; Velásquez, Zahady D.; Colenso, Charlotte K.; Brauchi, Sebastián; Burgos, Rafael A.; Hidalgo, María A.

doi:10.1371/journal.pone.0119715

Cited by 26 publications

(46 citation statements)

References 51 publications

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“…Neutrophils are the only tissue in which GPR40 was detected. Since GPR40 has already been implicated in calcium-dependent degranulation and superoxide production in bovine neutrophils [ 53 ], its presence was certainly expected. Its downregulation over time suggests lower PMNL activity postpartum.…”

Section: Discussionmentioning

confidence: 99%

Expression of fatty acid sensing G-protein coupled receptors in peripartal Holstein cows

Agrawal

Alharthi

Vailati-Riboni

et al. 2017

J Animal Sci Biotechnol

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BackgroundG-protein coupled receptors (GPCR), also referred as Free Fatty Acid Receptors (FFAR), are widely studied within human medicine as drug targets for metabolic disorders. To combat metabolic disorders prevalent in dairy cows during the transition period, which co-occur with negative energy balance and changes to lipid and glucose metabolism, it may be helpful to identify locations and roles of FFAR and other members of the GPCR family in bovine tissues.ResultsQuantitative RT-PCR (qPCR) of subcutaneous adipose, liver, and PMNL samples during the transition period (-10, +7, and +20 or +30 d) were used for expression profiling of medium- (MCFA) and long-chain fatty acid (LCFA) receptors GPR120 and GPR40, MCFA receptor GPR84, and niacin receptor HCAR2/3. Adipose samples were obtained from cows with either high (HI; BCS ≥ 3.75) or low (LO; BCS ≤ 3.25) body condition score (BCS) to examine whether FFAR expression is correlated with this indicator of health and body reserves. Supplementation of rumen-protected methionine (MET), which may improve immune function and production postpartum, was also compared with unsupplemented control (CON) cows for liver and blood polymorphonuclear leukocytes (PMNL) samples. In adipose tissue, GPR84 and GPR120 were differentially expressed over time, while GPR40 was not expressed; in PMNL, GPR40 was differentially expressed over time and between MET vs. CON, GPR84 expression differed only between dietary groups, and GPR120 was not expressed; in liver, GPCR were either not expressed or barely detectable.ConclusionsThe data indicate that there is likely not a direct role in liver for the selected GPCR during the transition period, but they do play variable roles in adipose and PMN. In future, these receptors may prove useful targets and/or markers for peripartal metabolism and immunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s40104-017-0150-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Expression of fatty acid sensing G-protein coupled receptors in peripartal Holstein cows

Agrawal

Alharthi

Vailati-Riboni

et al. 2017

J Animal Sci Biotechnol

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“…Studies of FFAR1/GPR40 in pancreatic b cells (human, mouse or rat) have demonstrated that FFAR1/GPR40 activation stimulates PLC and intracellular calcium. 42 Human FFAR1, which shows 85% identity with the bovine receptor, 10 induced PI3K, ERK1/2 and p38 MAPK activation. 19 In bovine neutrophils, natural and synthetic ligands of FFAR1/GPR40 stimulated intracellular calcium mobilization and PLC and PKC activation, 10 pathways that have been associated with MAPK activation.…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophils (1 Â 10 6 ) were incubated with 10 mM UO126, 10 mM SB203580, 10 mM LY294002 or vehicle (0.1% DMSO) for 5 min at 37 C, and then with FFAR1/GPR40 agonists (10 mM GW9508, 100 mM LA or 300 mM OLA) for 5 min at 37 C. After incubation, the neutrophils were centrifuged at 600 g for 6 min, and equal amounts of supernatants were assayed for gelatinase activity by zymography, as described. 10 Briefly, 10 ml supernatant was loaded on 10% polyacrylamide gels (0.75-mm thick) containing 0.2% gelatine. The gels were run at 200 V for 1 h in a Bio-Rad Mini Protean II apparatus (Bio-Rad Laboratories, Richmond, CA, USA) and then soaked twice in 2.5% Triton X-100 in distilled water on a shaker at room temperature for 30 min.…”

Section: Determination Of Mmp-9 Activity By Zymographymentioning

confidence: 99%

“…6,7 In bovine neutrophils, the unsaturated fatty acids oleic (OLA) and linoleic (LA) acid increase ROS production, matrix metalloproteinase (MMP)-9 release, and cyclooxygenase (COX)-2 and IL-8 mRNA levels. [8][9][10] OLA and LA-induced ROS and MMP-9 release are mediated through free fatty acid receptor-1 (FFAR1/ GPR40). FFAR1/GPR40 is a G protein-coupled receptor that has been identified in pancreatic cells, [11][12][13] monkey neurons, 14 breast cancer cells, 15,16 and bovine mammary epithelial cells and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

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Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

et al. 2016

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Fatty acids have been recognized as regulators of immune function in addition to their known metabolic role. Long-chain fatty acids bind free fatty acid receptor (FFAR)-1/GPR40, which is expressed on bovine neutrophils, and increase responses such as granule release and gene expression. In this study, we investigated the molecular mechanisms governing the up-regulation of cyclooxygenase-2 (COX-2) and IL-8, as well as matrix metalloproteinase (MMP)-9 granule release in FFAR1/GPR40 agonist-stimulated neutrophils. Our results showed that natural (oleic and linoleic acid) and synthetic (GW9508) FFAR1/GPR40 agonists increased ERK1/2, p38 MAPK and Akt phosphorylation, and that the FFAR1/GPR40 antagonist GW1100 reduced these responses. We evaluated the levels of IκBα, a component of the classical activation pathway of the transcription factor NF-κB, and we observed IκBα reduction after stimulation with FFAR1/GPR40 agonists, an effect that was inhibited by GW1100 or the inhibitors UO126, SB203580 or LY294002. FFAR1/GPR40 agonists increased COX-2 and IL-8 expression, which was inhibited by GW1100 and an NF-κB inhibitor. Finally, the FFAR1/GPR40 agonist-induced MMP-9 granule release was reduced by GW1100 and UO126. In conclusion, FFAR1/GPR40 agonists differentially stimulate neutrophil functions; COX-2 and IL-8 are expressed after FFAR1/GPR40 activation via NF-κB, IκBα reduction is FFAR1/GPR40- and PI3K/MAPK-dependent, and MMP-9 granule release is FFAR1/GPR40- and ERK1/2-dependent.

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“…However, we still cannot rule out the possibility that there might be other regulatory mechanisms underlying the OA‐induced MMP upregulation seen in cultured VSMCs. Intriguingly, OA is recently found to upregulate MMP‐9 release from human neutrophils through a FFA receptor 1 (FFAR1)‐regulated mechanism [Manosalva et al, ]. Our unpublished data demonstrated that treatment with TAK‐875, an FFAR1 agonist, but not with TUG‐891, an FFAR4 agonist, significantly increased LOX‐1 expression in cultured VSMCs (Fig.…”

Section: Discussionmentioning

confidence: 57%

Free Fatty Acids Induce Autophagy and LOX‐1 Upregulation in Cultured Aortic Vascular Smooth Muscle Cells

Cheng

Lee

Chen

et al. 2017

J of Cellular Biochemistry

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Elevation of free fatty acids (FFAs) is known to affect microvascular function and contribute to obesity-associated insulin resistance, hypertension, and microangiopathy. Proliferative and synthetic vascular smooth muscle cells (VSMCs) increase intimal thickness and destabilize atheromatous plaques. This study aimed to investigate whether saturated palmitic acid (PA) and monounsaturated oleic acid (OA) modulate autophagy activity, cell proliferation, and vascular tissue remodeling in an aortic VSMC cell line. Exposure to PA and OA suppressed growth of VSMCs without apoptotic induction, but enhanced autophagy flux with elevation of Beclin-1, Atg5, and LC3I/II. Cotreatment with autophagy inhibitors potentiated the FFA-suppressed VSMC growth and showed differential actions of PA and OA in autophagy flux retardation. Both FFAs upregulated lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) but only OA increased LDL uptake by VSMCs. Mechanistically, FFAs induced hyperphosphorylation of Akt, ERK1/2, JNK1/2, and p38 MAPK. All pathways, except OA-activated PI3K/Akt cascade, were involved in the LOX-1 upregulation, whereas blockade of PI3K/Akt and MEK/ERK cascades ameliorated the FFA-induced growth suppression on VSMCs. Moreover, both FFAs exhibited tissue remodeling effect through increasing MMP-2 and MMP-9 expression and their gelatinolytic activities, whereas high-dose OA significantly suppressed collagen type I expression. Conversely, siRNA-mediated LOX-1 knockdown significantly attenuated the OA-induced tissue remodeling effects in VSMCs. In conclusion, OA and PA enhance autophagy flux, suppress aortic VSMC proliferation, and exhibit vascular remodeling effect, thereby leading to the loss of VSMCs and interstitial ECM in vascular walls and eventually the instability of atheromatous plaques. J. Cell. Biochem. 118: 1249-1261, 2017. © 2016 Wiley Periodicals, Inc.

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Cloning, Identification and Functional Characterization of Bovine Free Fatty Acid Receptor-1 (FFAR1/GPR40) in Neutrophils

Cited by 26 publications

References 51 publications

Expression of fatty acid sensing G-protein coupled receptors in peripartal Holstein cows

Expression of fatty acid sensing G-protein coupled receptors in peripartal Holstein cows

Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

Free Fatty Acids Induce Autophagy and LOX‐1 Upregulation in Cultured Aortic Vascular Smooth Muscle Cells

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