Regulation of the GPR40 locus: towards a molecular understanding

Abstract

GPR40 {FFAR1 [non-esterified ('free') fatty acid receptor 1]} is a G-protein-coupled receptor expressed preferentially in pancreatic beta-cells. GPR40 functions as a receptor for medium and long-chain fatty acids, and has been implicated in mediating both physiological and pathological effects of fatty acids on beta-cells. The GPR40 gene is encoded at an interesting chromosomal locus that contains several genes: at the 5'-end of the locus, located approximately 4 kb upstream of GPR40, is CD22, a gene encoding a receptor expressed selectively in lymphocytes and involved in B-lymphocyte maturation and function. At the 3'-end of the locus are the GPR41 (FFAR3) and GPR43 (FFAR2) genes encoding receptors activated by short-chain fatty acids. The intergenic region between CD22 and GPR40 contains several evolutionarily conserved sequence blocks, among them HR2 and HR3. beta-Cell-specific expression of GPR40 is controlled at the transcriptional level through HR2, a potent beta-cell-specific enhancer. The mechanisms controlling cell-specific expression of the remaining genes in the cluster are unknown. Given the divergent modes of expression of the genes within the locus and their demonstrated physiological significance, it is important to analyse further the locus with a view to fully understanding the basis for transcriptional regulation of the encoded genes.

International Union of Pharmacology. LXXI. Free Fatty Acid Receptors FFA1, -2, and -3: Pharmacology and Pathophysiological Functions

“…Expression has also been detected in rat islets (Salehi et al, 2005;Feng et al, 2006). Such prominent ␤-cell expression was explained by a recent study on the promoter region of FFA1 that showed several highly conserved regions, one of which, HR2, is known to be a potent ␤-cell-specific enhancer of transcription (BartoovShifman et al, 2007;Ridner et al, 2008). Although none of the initial articles on the expression pattern of FFA1 were able to detect expression of the receptor within the glucagon-producing ␣-cells of islets, a more recent report using a prospective FFA1 antibody showed the receptor to colocalize with glucagon, suggesting that the receptor can be found within ␣-cells (Flodgren et al, 2007).…”

Physiological Appetite Regulation and Bariatric Surgery

“…The distribution of GPR40 suggests it may act to regulate pancreatic islet and neurological cell function [ 62 ]. Close to the GPR40 locus are the GPR41 and GPR43 genes encoding receptors activated by short-chain fatty acids [ 63 ]. GPCR receptors linked to GIP secretion are GPR120 and GPR40, expressed in K cells in the upper small intestine [ 64 , 65 ].…”

GPR40: A therapeutic target for mediating insulin secretion

“…Three evolutionarily conserved sequences (HR1-HR3) are located upstream of the first exon. Among these, HR2 is a potent β-cell-specific enhancer and binds transcription factors, PDX1 and BETA2, and is thus responsible for regulating the transcriptional levels of the gene in β-cells (34,35). GPR40 belongs to class A GPRs, showing a typical 7-transmembrane (TM) domain structure spanning α-helices with 3 hydrophilic intracellular and 3 hydrophilic extracellular loops.…”