Free fatty acid receptor

Last updated
free fatty acid receptor 1
Identifiers
SymbolFFAR1, FFA1R
Alt. symbolsGPR40
NCBI gene 2864
HGNC 4498
OMIM 603820
RefSeq NM_005303
UniProt O14842
Other data
Locus Chr. 19 q13.1
Search for
Structures Swiss-model
Domains InterPro
free fatty acid receptor 2
Identifiers
SymbolFFAR2
Alt. symbolsGPR43, FFA2R
NCBI gene 2867
HGNC 4501
OMIM 603823
RefSeq NM_005306
UniProt O15552
Other data
Locus Chr. 19 q13.1
Search for
Structures Swiss-model
Domains InterPro
free fatty acid receptor 3
Identifiers
SymbolFFAR3
Alt. symbolsGPR41, FFA3R
NCBI gene 2865
HGNC 4499
OMIM 603821
RefSeq NM_005304
UniProt O14843
Other data
Locus Chr. 19 q13.1
Search for
Structures Swiss-model
Domains InterPro
free fatty acid receptor 4
Identifiers
SymbolFFAR4
Alt. symbolsBMIQ10, GPR120, GPR129, GT01, O3FAR1, PGR4, free fatty acid receptor 4
NCBI gene 338557
OMIM 609044
RefSeq NM_181745
UniProt Q5NUL3
Other data
Locus Chr. 10 q23.33
Search for
Structures Swiss-model
Domains InterPro
G protein-coupled receptor 42
Identifiers
SymbolGPR42
Alt. symbolsGPR41L, FFAR1L
NCBI gene 2866
HGNC 4500
OMIM 603822
RefSeq NM_005305
UniProt O15529
Other data
Locus Chr. 19 q31.1
Search for
Structures Swiss-model
Domains InterPro

Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs). [1] GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large 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 express more than 800 different types of GPCRs. [3] FFARs are GPCR that bind and thereby become 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 with each carbon being bound to 1, 2 or 3 hydrogens (CH1, CH2, or CH3). [4] For example, propionic acid is a short-chain fatty acid consisting of 3 carbons (C's), CH3-CH2-COOH, and docosahexaenoic acid is a very long-chain polyunsaturated fatty acid consisting of 22 C's and six double bonds (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. [5]

Contents

Currently, four FFARs are recognized: FFAR1, also termed GPR40; FFAR2, also termed GPR43; FFAR3, also termed GPR41; and FFAR4, also termed GPR120. [6] The human FFAR1, FFAR2, and FFAR3 genes are located close 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 (previously termed the FFAR1L, FFAR3L, GPR41L, and GPR42P gene). This gene appears to be a segmental duplication of the FFAR3 gene. The human GPR42 gene codes for several proteins with a FFAR3-like structure but their expression in various cell types and tissues as well as their activities and functions have not yet been clearly defined. Consequently, none of these proteins are classified as an FFAR. [7] [8] [9] [10] The human FFAR1 gene is located on the long (i.e. "q") arm of chromosome 10 (notated as 10q23.33). [11]

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, proprionic, pentanoic, and hexanoic acids. [7] [12] [13] β-hydroxybutyric acid has been reported to stimulate or inhibit FFAR3. [14] 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 and capric acids [15] and long-chain or very long-chain fatty acids (i.e., fatty acids consisting respectively of 13 to 21 or more than 21 carbon atoms) such as myristic, steric, oleic, palmitic, palmitoleic, linoleic, alpha-linolenic, dihomo-gamma-linolenic, eicosatrienoic, arachidonic (also termed eicosatetraenoic acid), eicosapentaenoic, docosatetraenoic, docosahexaenoic, [4] [13] [16] and 20-hydroxyeicosatetraenoic acids. [17] Among the fatty acids that activate FFAR1 and FFAR4, docosahexaenoic and eicosapentaenoic acids are regarded as the main fatty acids that do so. [18]

Many of the FFAR-activating fatty acids also activate other types of GPRs. The actual GPR activated by a fatty acid must be identified in order to understand its and the activated GPR's function. The following section gives the non-FFAR GPRs that are activated by FFAR-activating fatty acids. One of the most often used and best way of showing that a fatty acid's action is due to a specific GPR is to show that the fatty acid's action is either absent or significantly reduced in cells, tissues, or animals that have no or significantly reduced activity due, respectively, to the knockout (i.e., total removal or inactivation) or knockdown (i.e., significant depression ) of the gene's GPR protein that mediates the fatty acid's action. [13] [19] [20]

Other GPRs activated by FFAR-activating fatty acids

GPR84 binds and is activated by medium-chain fatty acids consisting of 9 to 14 carbon atoms such as capric, undecaenoic, and lauric acids. [21] [22] It has been recognized as a possible member of the free fatty acid receptor family in some publications [23] but has not yet been given this designation perhaps because these medium-chain fatty acid activators require very high concentrations (e.g., in the micromolar range) to activate it. This allows that there may be a naturally occurring agent(s) that activates GPR84 at lower concentrations than the cited fatty acids. [24] Consequently, GPR89 remains classified as an orphan receptor, i.e., a receptor who's naturally occurring activator(s) is unclear. [22]

GPR109A is also termed hydroxycarboxylic acid receptor 2, niacin receptor 1, HM74a, HM74b, and PUMA-G. [25] GPR109A binds and thereby is activated by the short-chain fatty acids, butyric, β-hydroxybutyric, [26] [27] pentanoic and hexanoic acids and by the intermediate-chain fatty acids heptanoic and octanoic acids. [28] GPR109A is also activated by niacin but only at levels that are in general too low to activate it unless it is given as a drug in high doses. [26] [29]

GPR81 (also termed hydroxycarboxylic acid receptor 1, HCAR1, GPR104, GPR81, LACR1, TA-GPCR, TAGPCR, and FKSG80) binds and is activated by the short-chain fatty acids, lactic acid [30] [31] and β-hydroxybutyric acid. [32] A more recent study reported that it is also activated by the compound 3,5-dihydroxybenzoic acid. [33]

GPR109B (also known as hydroxycarboxylic acid receptor 3, HCA3, niacin receptor 2, and NIACR2) binds and is activated by the medium-chain fatty acid, 3-hydroxyoctanoate, [34] niacin, [35] and by four compounds viz., hippuric acid, [35] 4-hydroxyphenyllactic acid, phenyllacetic acid, and indole-3-lactic acid. [36] The latter three compounds are produced by Lactobacillus and Bifidobacterium species of bacteria that occupy the gastrointestinal tracts of animals and humans. [36]

GPR91 (also termed the succinic acid receptor, succinate receptor, or SUCNR1) is activated most potently by the short-chain dicarobxylic fatty acid, succinic acid; the short-chain fatty acids, oxaloacetic, malic, and α-ketoglutaric acids are less potent activators of GPR91. [37]

Related Research Articles

<span class="mw-page-title-main">Butyric acid</span> Chemical compound

Butyric acid, also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2CO2H. It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid is an isomer. Salts and esters of butyric acid are known as butyrates or butanoates. The acid does not occur widely in nature, but its esters are widespread. It is a common industrial chemical and an important component in the mammalian gut.

<span class="mw-page-title-main">CD36</span> Mammalian protein found in Homo sapiens

CD36, also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.

<span class="mw-page-title-main">Formyl peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

<span class="mw-page-title-main">GPR31</span> Protein in humans

G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.

<span class="mw-page-title-main">GPR32</span> Human biochemical receptor

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

<span class="mw-page-title-main">Free fatty acid receptor 1</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">Free fatty acid receptor 3</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 3 protein is a G protein coupled receptor that in humans is encoded by the FFAR3 gene. GPRs reside on cell surfaces, bind specific signaling molecules, and thereby are activated to trigger certain functional responses in their parent cells. FFAR3 is a member of the free fatty acid receptor group of GPRs that includes FFAR1, FFAR2, and FFAR4. All of these FFARs are activated by fatty acids. FFAR3 and FFAR2 are activated by certain short-chain fatty acids (SC-FAs), i.e., fatty acids consisting of 2 to 6 carbon atoms whereas FFFAR1 and FFAR4 are activated by certain fatty acids that are 6 to more than 21 carbon atoms long. Hydroxycarboxylic acid receptor 2 is also activated by a SC-FA that activate FFAR3, i.e., butyric acid.

<span class="mw-page-title-main">GPR42</span> Protein-coding gene in the species Homo sapiens

Putative G-protein coupled receptor 42 is a protein that in humans is encoded by the GPR42 gene. The human GPR gene is located at the same site as the human FFAR1, FFAR, and FFAR3 genes, i.e., on the long arm of chromosome 19 at position 23.33. This gene appears to be a segmental duplication of the FFAR3 gene. The human GPR42 gene codes for several proteins with a FFAR3-like structure but their expression in various cell types and tissues as well as their activities and functions have not yet been clearly defined in any scientific publication followed by PubMed as of 2023.

<span class="mw-page-title-main">Free fatty acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 2 (FFAR2), also termed G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor. It is coded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12. Like other GPCRs, FFAR2s reside on the surface membrane of cells and when bond to one of their activating ligands regulate the function of their parent cells. FFAR2 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes three other receptors which, like FFAR2, are activated by certain fatty acids: FFAR1, FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids whereas FFAR1 and FFAR4 are activated by long-chain fatty acids.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 3</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 3 (HCA3), also known as niacin receptor 2 (NIACR2) and GPR109B, is a protein which in humans is encoded by the HCAR3 gene. HCA3, like the other hydroxycarboxylic acid receptors HCA1 and HCA2, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonists of HCA3 are 3-hydroxyoctanoic acid and kynurenic acid. HCA3 is also a low-affinity biomolecular target for niacin (aka nicotinic acid).

<span class="mw-page-title-main">GPR132</span> Protein-coding gene in the species Homo sapiens

G protein coupled receptor 132, also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e. GPR4, GPR68 (OGR1), and GPR65 (TDAG8), G2A is a G protein coupled receptor that resides in the cell surface membrane, senses changes in extracellular pH, and can alter cellular function as a consequence of these changes. Subsequently, G2A was suggested to be a receptor for lysophosphatidylcholine (LPC). However, the roles of G2A as a pH-sensor or LPC receptor are disputed. Rather, current studies suggest that it is a receptor for certain metabolites of the polyunsaturated fatty acid, linoleic acid.

<span class="mw-page-title-main">GPR84</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.

<span class="mw-page-title-main">Free fatty acid receptor 4</span> Protein-coding gene in the species Homo sapiens

Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1, FFAR2, and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">Oxoeicosanoid receptor 1</span> Protein-coding gene in the species Homo sapiens

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.

<span class="mw-page-title-main">LPAR3</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 3 also known as LPA3 is a protein that in humans is encoded by the LPAR3 gene. LPA3 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

<span class="mw-page-title-main">Sodium-coupled monocarboxylate transporter 1</span> Protein-coding gene in the species Homo sapiens

Sodium-coupled monocarboxylate transporter 1 (i.e., SMCT1) and sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2) are plasma membrane transport proteins in the solute carrier family. They transport sodium cations in association with the anionic forms (see conjugated base) of certain short-chain fatty acids (i.e., SC-FAs) through the plasma membrane from the outside to the inside of cells. For example, propionic acid (i.e., CH
3CH
2CO
2H) in its anionic "propionate" form (i.e., CH
3CH
2CO−
2) along with sodium cations (i.e., Na+) are co-transported from the extracellular fluid into a SMCT1-epxressing cell's cytoplasm. Monocarboxylate transporters (MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with proton cations (i.e. H+). Four of the 14 MCTs, i.e. SLC16A1 (i.e., MCT1), SLC16A7 (i.e., MCT22), SLC16A8 (i.e., MCT3), and SLC16A3 (i.e., MCT4), transport some of the same SC-FAs anions that the SMCTs transport into cells. SC-FAs do diffuse into cells independently of transport proteins but at the levels normally occurring in tissues far greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.

The hydroxycarboxylic acid receptor (abbreviated HCA receptor and HCAR) family includes the following human proteins:

Sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2, also termed SLC5A12) is a plasma membrane transport protein in the solute carrier family. It transports sodium cations (i.e., Na+) in association with the anionic forms (see conjugated base) of certain short-chain fatty acids (i.e., SC-FAs) and other agents through the plasma membrane from the outside to the inside of cells. The only other member of the sodium-coupled monocarboxylate transporter group (sometimes referred to as the SLC5A family), SMCT1, similarly co-transports SC-FAs and other agents into cells. Monocarboxylate transporters (MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with hydrogen cations (i.e. H+). Four of the 14 MCTs, i.e. SLC16A1 (i.e., MCT1), SLC16A7 (i.e., MCT22), SLC16A8 (i.e., MCT3), and SLC16A3 (i.e., MCT4), transport some of the same SC-FAs anions that the two SMCTs transport into cells. SC-FAs do diffuse into cells independently of transport proteins but at the levels normally occurring in tissues greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.

References

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  2. ↑ Weis WI, Kobilka BK (June 2018). "The Molecular Basis of G Protein-Coupled Receptor Activation". Annual Review of Biochemistry. 87: 897–919. doi:10.1146/annurev-biochem-060614-033910. PMC   6535337 . PMID   29925258.
  3. ↑ Liang C, Li J, Tian B, Tian L, Liu Y, Li J, Xin L, Wang J, Fu C, Shi Z, Xia J, Liang Y, Wang K (December 2021). "Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment". Biomedicine & Pharmacotherapy. 144: 112298. doi: 10.1016/j.biopha.2021.112298 . PMID   34649219. S2CID   238990829.
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