Regulation of the GPR40 locus: towards a molecular understanding

GPR40 {FFAR1 [non-esterified (‘free’) fatty acid receptor 1]} is a G-protein-coupled receptor expressed preferentially in pancreatic β-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 β-cells. The GPR40 gene is encoded at an interesting chromosomal locus that contains several genes: at the 5′-end of the locus, located ∼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. β-Cell-specific expression of GPR40 is controlled at the transcriptional level through HR2, a potent β-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.