Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

Shi, Guojun; Sun, Chen; Gu, Weiqiong; Yang, Mei; Zhang, Xiaofang; Zhai, Nan; Lü, Yan; Zhang, Zhijian; Shou, Peishun; Zhang, Zhiguo; Ning, Guang

doi:10.1530/jme-14-0065

Cited by 34 publications

(41 citation statements)

References 47 publications

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“…GPR43 expression appears to be modulated during inflammation as immune challenge by lipopolysaccharide (LPS) or tumor necrosis factor (TNF), or treatment with granulocyte-macrophage colony stimulating factor (GM-CSF), was found to raise GPR43 transcript levels in human monocytes ( 20 , 21 ). Consistently, luciferase reporter assays have identified inflammation-associated NF-κB ( 22 ) and XBP1 ( 21 ) transcription factor-binding sites within the GPR43 promoter.…”

Section: Gpr41 and Gpr43 Expression Is Tissue-specificmentioning

confidence: 73%

GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative?

Ang¹,

Ding²

2016

Front. Immunol.

239

161

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GPR41 and GPR43 are a pair of mammalian G protein-coupled receptors (GPCRs) expressed in human adipocytes, colon epithelial cells, and peripheral blood mononuclear cells. These receptors are activated by short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate – which are produced during dietary fiber fermentation by resident gut bacteria. This unique ligand specificity suggests that GPR41 and GPR43 may mediate the interaction between the human host and the gut microbiome. Indeed, studies on knockout mice implicate GPR41 and GPR43 in chronic inflammatory disorders such as obesity, colitis, asthma and arthritis. However, whether GPR41 and GPR43 are protective or causative is inconsistent between studies. This discrepancy may be due to differences in the disease models used, the inbred mouse strains, or non-specific knockout effects. Here, we review the latest findings on GPR41 and GPR43, highlighting contradictory observations. With GPR41 and GPR43 being considered as drug targets, it is pertinent that their role is fully elucidated. We propose that future studies on human tissues, ex vivo, may allow us to confirm the role of GPR41 and GPR43 in humans, be it protective or causative.

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Section: Gpr41 and Gpr43 Expression Is Tissue-specificmentioning

confidence: 73%

GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative?

Ang¹,

Ding²

2016

Front. Immunol.

239

161

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show abstract

“…Indeed, bovine and murine tissue specific expression of GPR43 have been found to be highly similar to that of the human counterpart 14 15 16 46 . A recent study reported transcriptional activity from a luciferase assay of a 500 bp sequence immediately upstream of the human GPR43 start codon in mouse RAW264.7 macrophages 47 . Interestingly, these researchers predicted an NF-κB binding site within this 500-bp sequence, although the mutation was reported to cause only 10% reduction in the promoter activity.…”

Section: Discussionmentioning

confidence: 99%

The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes

Ang

Ding

2015

Sci Rep

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G-protein coupled receptor 43 (GPR43) recognizes short chain fatty acids and is implicated in obesity, colitis, asthma and arthritis. Here, we present the first full characterization of the GPR43 promoter and 5′-UTR. 5′-RACE of the GPR43 transcript identified the transcription start site (TSS) and a 124 bp 5′-UTR followed by a 1335 bp intron upstream of the ATG start codon. The sequence spanning -4560 to +68 bp relative to the GPR43 TSS was found to contain strong promoter activity, increasing luciferase reporter expression by >100-fold in U937 monocytes. Stepwise deletions further narrowed the putative GPR43 promoter (−451 to +68). Site-directed mutagenesis identified XBP1 as a core cis element, the mutation of which abrogated transcriptional activity. Mutations of predicted CREB, CHOP, NFAT and STAT5 binding sites, partially reduced promoter activity. ChIP assays confirmed the binding of XBP1 to the endogenous GPR43 promoter. Consistently, GPR43 expression is reduced in monocytes upon siRNA-knockdown of XBP1, while A549 cells overexpressing XBP1 displayed elevated GPR43 levels. Based on its ability to activate XBP1, we predicted and confirmed that TNFα induces GPR43 expression in human monocytes. Altogether, our findings form the basis for strategic modulation of GPR43 expression, with a view to regulate GPR43-associated diseases.

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“…Its activation appears to be regulated during inflammation by LPS or TNF-α, which have shown to raise GPR43 levels in human monocytes (5,141). Consistently, luciferase reporter assays have identified inflammation-associated NFκB transcription factor-binding sites within the GPR43 promoter (143). GPR43 is expressed in intestine and adipose tissue, where it has been proposed to play a role in secretion of hormones and regulation of appetite (148).…”

Section: Gpr43 (Ffar2)mentioning

confidence: 75%

The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

Recio

Lucy

Iqbal

et al. 2018

Antioxidants & Redox Signaling

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Great attention has been placed on the link between metabolism and immune function giving rise to the term "immunometabolism." It is widely accepted that inflammation and oxidative stress are key processes that underlie metabolic complications during obesity, diabetes, and atherosclerosis. Therefore, identifying the mechanisms and mediators that are involved in the regulation of both inflammation and metabolic homeostasis is of high scientific and therapeutic interest. Recent Advances: G protein-coupled receptors (GPCRs) that signal in response to metabolites have emerged as attractive therapeutic targets in inflammatory disease. Critical Issues and Future Directions: In this review, we discuss recent findings about the physiological role of the main metabolite-sensing GPCRs, their implication in immunometabolic disorders, their principal endogenous and synthetic ligands, and their potential as drug targets in inflammation and metabolic disease. Antioxid. Redox Signal. 29, 237-256.

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Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

Cited by 34 publications

References 47 publications

GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative?

GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative?

The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes

The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

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