Disease relevance of FFAR2

• Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line [1].
• In contrast, the highly selective expression of GPR43 in leukocytes, particularly polymorphonuclear cells, suggests a role in the recruitment of these cell populations toward sites of bacterial infection [2].
• They exhibited, however, a differential coupling to G proteins; GPR41 coupled exclusively though the Pertussis toxin-sensitive Gi/o family, whereas GPR43 displayed a dual coupling through Gi/o and Pertussis toxin-insensitive Gq protein families [2].
• These common themes implicate GPR40, GPR41 and GPR43 in playing significant roles in metabolic diseases, such as diabetes, obesity and the metabolic syndrome [3].

High impact information on FFAR2

• These results suggest that LSSIG and GPR43 might play pivotal roles in differentiation and immune response of monocytes and granulocytes [4].
• Cytokine-stimulation induced LSSIG and GPR43 in bone marrow cells, and monocytes and neutrophils, respectively [4].
• GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist [5].
• This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca(2+) mobilization and [(35)S]guanosine 5'-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes [5].
• Acetate was more selective for GPR43, whereas butyrate and isobutyrate were more active on GPR41 [2].

Biological context of FFAR2

• Propionate induced elevations in intracellular Ca(2+) and the phosphorylation of p38 were inhibited by the silencing of GPR43 using a specific siRNA [1].
• The pharmacology of GPR43 matches indeed the effects of SCFAs on neutrophils, in terms of intracellular Ca2+ release and chemotaxis [2].
• In conclusion, SCFAs can modulate intestinal motility, but these effects can be independent of the GPR43 receptor [6].
• GPR41 and GPR43 have been reported to stimulate leptin release and adipogenesis respectively via activation by short-chain fatty acids [3].

Anatomical context of FFAR2

• Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids [7].
• GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells [5].
• GPR43 expression was also strongly induced in HL-60 and U937 leukemia cells during the differentiation to monocytes [4].
• Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine [8].
• The results of the present study suggest that the PYY-containing enteroendocrine cells and 5-HT-containing mucosal mast cells sense SCFAs via the GPR43 receptor [8].

Associations of FFAR2 with chemical compounds

• Propionate was the most potent agonist for both GPR41 and GPR43 [2].
• In each model, the rank-order of activity was acetate (C2) approximately propionate (C3) approximately butyrate (C4) > pentanoate (C5) approximately formate (C1), consistent with activity at the GPR43 receptor [6].

Analytical, diagnostic and therapeutic context of FFAR2

• GPR43 protein was detected by Western blot analysis in extracts of whole wall and separated mucosa, but not in muscle plus submucosa extracts [8].

References