Free fatty acid receptor

Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs).[1] GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large protein family of receptors. They reside on their parent cells' surface membranes, bind any one of a specific set of ligands that they recognize, and thereby are activated to elicit certain types of responses in their parent cells.[2] Humans have >800 different types of GPCR receptors.[3] The FFARs are GPCR receptors that bind and thereby are activated by particular fatty acids. In general, these binding/activating fatty acids are straight-chain fatty acids consisting of a carboxylic acid residue, i.e., -COOH, attached to aliphatic chains, i.e. carbon atom chains of varying lengths and bound to 1, 2 or 3 hydrogens (CH1, CH2, or CH3).[4] For example, propionic acid is short-chain fatty acid consisting of 3 carbons (C's), CH3-CH2-COOH, and docosahexaenoic acid is long chain polyunsaturated fatty acid consisting of 22 C's and six double bonds (notated as "="): CH3-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH2-COOH.

Currently, four FFARs are recognized: FFAR1, also termed GPR40; FFAR2, also termed GPR43; FFAR3, also termed GPR41; and FFAR4, also termed GPR120.[5] The human FFAR1, FFAR2,, and FFAR3 genes are located adjacent to each other on the long (i.e., "q") arm of chromosome 19 at position 23.33 (notated as 19q23.33). This location also includes the GPR42 gene which appears to be a segmental duplication of the FFAR3 gene; it encodes proteins with a FFAR3-like structure but their activities and functions have not yet been clearly defined.[6][7][8] The human FFAR1 gene is located on the arm long (i.e. "q") arm of chromosome 10 (notated as 10q23.33).[9] FFAR2 and FFAR3 bind and are activated by short-chain fatty acids, i.e., fatty acid chains consisting of 6 or less carbon atoms such as acetic, butyric, and propionic acids.[10] FFAR1 and FFAR4 bind to and are activated by medium-chain fatty acids (i.e. fatty acids consisting of 6-12 carbon atoms such as lauric acid[11]) as well as long-chain unsaturated fatty acids such as palmitic acid, monounsaturated fatty acids such as oleic acid, and polyunsaturated fatty acids such as linoleic, alpha-linolenic, eicosapentaenoic, and docosahexaenoic acids.[4]

Based on its binding and activation by medium-chain fatty acids i.e., capric acid, undecaenoic, and lauric acids,[12] GPR84 has been recognized as possible member of the free fatty acid receptor family.[13] However, GPR84 has not yet been given a FFAR designation possibly because capric acid, the most potent medium-chain fatty acid in activating GPR44, nonetheless requires high concentrations (e.g., in the micromolar range) to do so.[14]

GPR109A (also termed hydroxycarboxylic acid receptor 22, niacin receptor 1, HM74a, HM74b, or PUMA-G),[15] GPR91 (also termed the succinic acid receptor or SUCNR1), and GPR35 have been grouped with FFARs by some authors.[16] However, these receptors are more often defined as receptors primarily for non-straight-chain fatty acid ligands or physiological agents that are not fatty acids. GP109A binds and is activated by niacin, beta-hydroxybutyric acid, and butyric acid; it is often termed a hydroxycarboxylic acid receptor.[15] GPA91 binds and is activated by succinic acid.[3] And, GPR35, which remains classified as an orphan receptor (i.e., a receptor whose ligand(s) are not clearly identified) binds and is activated by a metabolite of tryptophan viz., kynurenic acid,[17] as well as by 5-hydroxyindoleacetic acid (a metabolite of serotonin) and various other small non-fatty acid molecules such as lysophosphatidic acid.[18] 5-Hydroxyindolacetic acid is a particularly potent activator of GPR35 and may be the most important of its naturally occurring activators.[18]