Free fatty acid receptor 1 (FFAR1) (FFAR1)

Free fatty acid receptor 1 (FFAR1), commonly referred to as GPR40, is a Class A G protein-coupled receptor that serves as a key sensor for medium- and long-chain fatty acids [1, 5]. It is predominantly expressed in pancreatic beta-cells, where its activation enhances glucose-stimulated insulin secretion (GSIS) in a glucose-dependent manner, thereby reducing the risk of hypoglycemia compared to other secretagogues [4, 13]. Additionally, GPR40 is found in enteroendocrine cells, where it triggers the release of incretin hormones such as GLP-1 and GIP, further supporting glucose homeostasis and satiety [11, 15]. Due to these roles, GPR40 has been a major therapeutic target for the treatment of type 2 diabetes and metabolic syndrome [1, 7]. However, the clinical advancement of early agonists like fasiglifam (TAK-875) was impeded by significant safety concerns regarding drug-induced liver injury (DILI) [8, 11]. This toxicity is believed to be compound-specific, involving mechanisms such as the formation of reactive acyl glucuronides and inhibition of mitochondrial function [2, 11]. Modern drug discovery efforts are now focused on identifying novel, liver-safe agonists and ago-allosteric modulators (AgoPAMs) that maintain high efficacy while avoiding the toxic metabolic pathways associated with previous candidates [2, 18]. Beyond metabolism, GPR40 may also play roles in bone homeostasis and anti-inflammatory responses via the inhibition of the NLRP3 inflammasome [5, 11].

Other names

G-protein coupled receptor 40GPCR40FFA1FFA1RFFAR1

Agonism of the G protein-coupled receptor, primarily through Gq-mediated signaling, which activates phospholipase C and increases intracellular calcium levels to potentiate glucose-stimulated insulin secretion [5, 7, 11]. Full agonists and ago-allosteric modulators (AgoPAMs) may also signal through Gs pathways to stimulate incretin release from the gut [11, 15, 18].