FFAR1 Membrane Protein Introduction

Introduction of FFAR1

FFAR1, also known as FFA1R or G-protein coupled receptor 40 (GPR40), is an approximately 31.5 kDa G-protein coupled receptor (GPCR) that has 300 amino acids length. In humans, this protein is encoded by the FFAR1 gene mapping at the cytogenetic band of chromosome 19q13.12. It belongs to the GP40 family of G protein-coupled receptors that plays an important role in glucose homeostasis. Free fatty acid (FFA) receptors are a group of Gq/11 protein-coupled receptors recently classified into four subtypes of FFA1, FFA2, FFA3, and FFA4. FFA receptors, essential for immunity and metabolism, are known to be concentrated in pancreatic islet cells and immune cell, as well as in the brain.

Function of FFAR1 Membrane Protein

FFAR1 is predominately expressed in pancreatic cells and in the brain. This membrane protein binds FFA, employed as a nutrient sensor for modulating energy homeostasis. FFAR1 is responsible for encoding medium and long-chain free fatty acids and is activated by carboxylic acids with carbon chain lengths greater than six. There is report shown that this receptor is specifically expressed in insulin-producing beta cells in the pancreas and may be implicated in the metabolic regulation of insulin secretion. FFAR1 can amplify glucose-dependent insulin secretion and thus, it has increasingly attracted attention as an attractive antidiabetic target. Furthermore, current clinical evidence of concept has indicated that FFAR1 agonists accomplish the initially therapeutic endpoint for the type 2 diabetes mellitus (T2DM) treatment without a hypoglycemic risk.

Fig.1 Structure of human FFAR1 in complex with the partial agonist MK-8666 and the AgoPAM AP8. (Lu, 2017)

Application of FFAR1 Membrane Protein in Literature

1. Li Z., et al. Free fatty acid receptor 1 (FFAR1) as an emerging therapeutic target for type 2 diabetes mellitus: recent progress and prevailing challenges. Med Res Rev. 2018, 38(2): 381-425. PubMed ID: 28328012.
   
   

   This review introduced the corresponding strategies chosen by diverse medicinal chemistry teams to promote the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief presentation to the pharmacology of associated targets.

2. Tunaru S., et al. 20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1. Nat Commun. 2018, 9(1): 177. PubMed ID: 29330456
   
   

   The authors showed that 20-hydroxyeicosatetraenoic acid (20-HETE) is a type of FFAR1 agonist, which serves as an autocrine positive feed-forward regulator of glucose-stimulated insulin secretion (GSIS), and that a decreased glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes.

3. Trauelsen M., et al. The HETE is on FFAR1 and pancreatic islet cells. Cell Metab. 2018, 27(2): 273-275. PubMed ID: 2 29414682
   
   

   It is unappreciated that the free fatty acid receptor 1 (FFAR1) is responsible for a central role of glucose-induced insulin secretion. This article is now explaining that glucose-induced 20-hydroxyeicosatetraenoic acid (20-HETE) enhances the secretion of insulin via autocrine activation of FFAR1.

4. Nakamoto K., et al. The role of brain n-3 fatty acids-GPR40/FFAR1 signaling in pain. Nihon Yakurigaku Zasshi. 2018, 151(1): 21-26. PubMed ID: 29321392
   
   

   Brain n-3 fatty acid-GPR40/FFAR1 signaling possibly plays a key part in the regulation of pain control system and emotional function. In this article, they discussed the role of brain n-3 fatty acids-GPR40/FFAR1 signaling in a pain and reviewed the current status and further prospects of GPR40/FFAR1 in the brain.

5. Darwish K. M., et al. Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists. Bioorg Med Chem Lett. 2018, 28(9): 1595-1602. PubMed ID: 29615345
   
   

   Recently the authors reported the discovery of three novel agents with balanced activity on two metabolic receptors, free fatty acid receptor 1 (FFAR1, also known as GPCR40) and peroxisome proliferator activated receptor-γ (PPAR-γ). Their designing strategy depended on linking the thiazolidinedione head with privileged GPCR structures.

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Reference

1. Lu J, et al. (2017). Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol. 24(7), 570-577.

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