Free fatty acid receptor 2 promotes cardiomyocyte hypertrophy by activating STAT3 and GATA4

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.

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

10.1101/776294 ◽

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.

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