The HETE Is on FFAR1 and Pancreatic Islet Cells Mette Trauelsen, Michael Lückmann, Thomas M. Frimurer, Thue W. Schwartz  Cell Metabolism  Volume 27, Issue 2, Pages 273-275 (February 2018) DOI: 10.1016/j.cmet.2018.01.006 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 20-HETE as a Glucose-Induced Autocrine Stimulator of Insulin Secretion through FFAR1 and Its Presumed Molecular Mechanism of Action (A) High glucose stimulates insulin secretion by increasing intracellular Ca2+ concentration through the classical pathway, including inhibition of ATP-sensitive K+ channels and downstream opening of Ca2+ channels (“direct” effect). However, Tunaru and coworkers now demonstrate that this at the same time activates phospholipase A2 (PLA2)to generate arachidonic acid, which subsequently is converted into 20-HETE by cytochrome P450-dependent ω-hydroxylases of the CYP2 and CYP4 families (CYP2/4). 20-HETE is exported from the β cell and acts in an autocrine fashion as an agonist on FFAR1 (GPR40), which though Gq/11 and phospholipase C (PLC-β) generation of IP3 and release of Ca2+ from the ER stores (not shown) stimulates insulin secretion further (+effect via 20-HETE & FFAR1) (Tunaru et al., 2018). The generation of 20-HETE is reduced in islets from diabetic rodents and type 2 diabetes patients as indicated. FFAR1 is also highly expressed on pancreatic α cells. A potential paracrine function of 20-HETE is indicated, although such a stimulatory effect most likely would be overruled by the well-established paracrine inhibitory effects of secretory products (insulin, Zn2+, GABA) from the β cells. In the middle are indicated the previously proposed potential stimulatory effects on FFAR1 expressed on both α and β cells of dietary triglyceride-derived LCFAs released from postprandial chylomicrons through the action of lipoprotein lipase (LPL) locally in the islet capillaries (Husted et al., 2017). The likely effect of free LCFAs generated from adipose tissue through lipolysis during fasting and consequently being high when glucose is low and thereby facilitating glucagon secretion from α cells is also indicated. Anna Sofie Husted is thanked for help in generating this figure. (B) Structures, binding sites, and signaling properties of FFAR1 agonist drug candidates and 20-HETE. Top blue box shows selected first-generation FFAR1 drug candidates fasiglifam (TAK-875) and MK-8666; top green box shows selected second-generation compounds AM-5262 and AP8. The structure of 20-HETE is indicated in the oval in the cytoplasm. The high-resolution X-ray structure of FFAR1 in complex with both MK-8666 and AP8 (Lu et al., 2017) is shown in side view with indication of the lipid bilayer. MK-8666-like TAK-875 binds in an extended hydrophobic pocket between transmembrane helix (TM) III and IV, where its carboxylate moiety reaches a highly polar, positively charged complex in the middle of the receptor while the “left side” of the compound is located in the outer leaflet of the lipid bilayer with the sulfone moiety reaching “up” toward the extracellular space. The ago-allosteric agonist AP8 binds in a highly lipid-exposed extrahelical site between the intracellular segments of TM IV and V where its carboxylate moiety stabilizes intracellular loop 2 (IC-Loop 2) in a helical conformation similar to the active conformation of the β2-adrenergic receptor (Lu et al., 2017). FFAR1 binding of first-generation synthetic ligands can, like the endogenous LCFAs including 20-HETE, only induce Gq and downstream IP3 signaling and are not able to stimulate GLP-1 secretion. In contrast, binding of second-generation FFAR1 agonists induces both IP3 and cAMP signaling and consequently strong hormone secretion including GLP-1 (Hauge et al., 2014). Most likely 20-HETE binds in the same site as MK-8666 and TAK-875 as they have similar signaling properties. Note that 20-HETE being generated within the β cell (A) in fact only needs to participate in the plasma membrane lipid bilayer to get access to the binding sites in FFAR1 (orange arrow), although it is also being released from the islet cells (Tunaru et al., 2018). Cell Metabolism 2018 27, 273-275DOI: (10.1016/j.cmet.2018.01.006) Copyright © 2018 Elsevier Inc. Terms and Conditions