Free fatty acid receptor 2

Source: Wikipedia, the free encyclopedia.
FFAR2
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000126262

ENSMUSG00000051314

UniProt

O15552

Q8VCK6

RefSeq (mRNA)

NM_005306
NM_001370087

NM_001168509
NM_001168510
NM_001168511
NM_001168512
NM_146187

RefSeq (protein)

NP_005297
NP_001357016

NP_001161981
NP_001161982
NP_001161983
NP_001161984
NP_666299

Location (UCSC)Chr 19: 35.44 – 35.45 MbChr 7: 30.52 – 30.52 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Free fatty acid receptor 2 (FFAR2), also termed G-protein coupled receptor 43 (GPR43), is a

long-chain fatty acids.[9]

Short-chain fatty acids (i.e., SCFAs) are made by intestinal bacteria (intestinal and intestine are used here to mean the

antibiotics, that reduce the intestinal levels of these bacteria.[10][9] It is now known that FFAR2 is activated by SCFAs and therefore may function not only in regulating normal body functions but also in inhibiting or promoting many diseases and disorders. Consequently, drugs are being tested for their ability to act more usefully, potently, and effectively than SCFAs to stimulate or inhibit FFAR2 for treating the conditions that appear inhibited or stimulated, respectively, by SCFAs.[12]

Studies have suggested that SCFA-activated FFAR2 regulates blood

neurological diseases,[13][14] and certain bacterial and viral infections.[15][16]
Here, we review studies on the functions of FFAR2 in health as well as these diseases and disorders.

Activators and inhibitors of FFAR2

FFAR2 and FFR3 are activated primarily by short-chain fatty acids (SCFAs) that are 2 to 6

hexanoic acid, which has 6 carbon atoms, is a weak activator of FFAR3[9] but its effect on FFAR2 has not been reported.[17] More recently, the ketone body fatty acid, acetoacetic acid, while not classified as a SCFA, has been shown to activate FFAR2 with a potency similar to acetic and propionic acids.[20]

Many drugs have been developed that bind to and regulate FFAR2's activity. 1) MOMBA, Sorbate,

GPR109A (now termed hydroxycarboxylic acid receptor 2 or HCA2), and two other GPRs, Olfr78 and Olfr558.[10] Most of the studies reported here include experiments in which the actions of SCFAs and FFAR2-regulating drugs in cells and animals are further tested in the cells and animals that have been made to express relatively little or no FFAR2 using gene knockdown or gene knockout
methods, respectively. The effects of SCFAs and the drugs should be reduced or absent in cells and animals that under-express or lack FFAR2.

Cells and tissues expressing FFAR2

Studies have detected FFAR2 protein and/or its

MCF7 breast cancer cells, Huh7 and JHH-4 liver cancer cells, THP-1 acute myeloid leukemia cells, U937 acute promyelocytic leukemia cells, and K562 myelogenous leukemia cells;[26] and 11) the various mouse and rat cell lines discussed below. FFAR2 is also expressed in a wide range of tissues in other animals such as cows, pigs, sheep, cats, and dogs.[26]

Formation of SCFAs

The oral administration of glucose elicits a much greater rise in blood insulin levels and a much lower rise in blood glucose levels than those elicited by

anaerobic bacteria[36]), ferment[24] these dietary fibers to form and then excrete SCFAs (primarily acetic, propionic, and butyric acids[37]).[38] The relative levels of these three SCFAs in the intestines of humans are about 60:20:20, respectively.[15] Intestinal SCFAs activate FFAR2-bearing cells in the nearby intestinal walls and also enter the blood circulation to activate FFAR2-bearing cells in distant tissues.[10] SCFAs may also be made and released by the bacteria and/or host cells in tissue that contain bacterial infections.[15]

FFAR2 functions and actions

Diabetes

Type 2 diabetes

The SCFAs excreted by the soluble dietary fiber-consuming bacteria in the intestine activate FFAR2 on nearby intestinal L-cells. This stimules these cells to secrete

GIP (i.e., glucose-dependent insulinotropic polypeptide). GIP stimulates insulin secretion but, perhaps paradoxically, also stimulates glucagon secretion; however, the net effect of GIP is to reduce blood glucose levels. GIP also slows gastric motility.[17][40] In addition, both GLP-1 and GIP protect pancreatic beta cells from dying by apoptosis (see programmed cell death).[17] The SCFAs excreted by the gut microorganisms also pass through the intestinal epithelium to enter the blood stream[37] and activate FFAR2 on cells located in distant tissues such as pancreas beta cells[39] and adipose tissue fat cells.[37]

Individuals with type 2 diabetes, particularly in advanced cases, have nearly completely lost the incretin effect.[41] A study treated non-diabetic, healthy men with the GLP-1 receptor antagonist (i.e., blocker of receptor activation) exendin(9-39)NH2a (also termed avexitide[42]), the GIP receptor antagonist GIP(3-30)NH2,[43] or both antagonists and challenged them with an oral glucose tolerance test. Men treated with either agent responded to the tolerance test with modest decreases in blood insulin levels and modest increases in blood glucose levels. However, men treated with both antagonists responded with very low insulin and very high glucose blood levels: their responses were similar to those in individuals with type 2 diabetes.[41][44] This study shows that 1) the stimulation of the FFAR2 on K and L cells by SCFAs underlies the differences between oral and intravenous glucose challenges defined by the incretin effect and 2) FFAR2 functions to regulate blood insulin and glucose levels. This does not prove that type 2 diabetes is a FFAR2-incretin disease: post-feeding secretion of the incretins (i.e.,GLP-1 and GIP) is impaired in type 2 diabetes, but the impairment appears to result primarily from decreases in the responsiveness of pancreas alpha cells to GLP-1. This conclusion is supported by studies showing that type 2 diabetic individuals who are treated with large amounts of GLP-1 and challenged with intravenous glucose show changes in blood insulin and glucose levels that are similar to those in non-diabetic individuals.[41] Indeed, GLP-1 agonists, e.g., Dulaglutide,[45] and a first-in-kind GLP-1 and GIP agonist, Tirzepatide,[46] are used to treat type 2 diabetes.

Type 1 diabetes

Ffar2

antigens) found that children who had low levels of SCFA-producing intestinal bacteria had a higher risk of progressing to type 1 diabetes than those with higher intestinal levels of these bacteria.[50] These results suggest that the activation of FFAR2 by intestinal SCFAs suppresses the development of type 1 diabetes in mice and humans and may do so by reducing the inflammation with injures pancreatic islet cells.[9][49][50][51]

Inflammation

FFAR2 is expressed in various cells involved in the development of

clinical studies that found the drug to be safe (i.e., non-toxic) but ineffective in reducing mild to moderate ulcerative colitis (further development of GLPG609 was terminated[58]).[18] While most studies suggest that FFAR2 suppresses human and mouse inflammation, further studies are needed to determine if and why FFAR2 promotes some types of inflammation.[9][26][55]

Adipogenesis, obesity, lipolysis, and ketogenesis

Angiogenesis and obesity

Studies have disagreed about the effects of FFAR2 on adipogenesis (i.e., formation of fat cells and fat tissue from precursor cells) as well as on the development of obesity.[9][24] The inconsistencies reported by different research groups need to be resolved through further research in order to develop a clear picture of the actions that FFAR2 has on adipogenesis and obesity.[24][55]

Lipolysis

Numerous studies have shown that SCFAs and FFAR2-activating drugs inhibit the lipolysis (i.e.,

fatty acids and glycerol) in mice and their cultured fat cells.[24] For example: acetic and propionic acids inhibited lipolysis in mice (as defined by reducing their fatty acid blood levels) as well as their isolated cultured fat cells but did not do so in Ffar2 gene knockout mice or their isolated fat cells.[24][59] There have been very few studies on FFAR2 and lipolysis in humans. Two studies reported that acetic acid suppressed fatty acid blood levels in humans but did not determine if this effect involved FFAR2.[59][60][61] Note that in a mouse model of severe stress, i.e., starvation, FFAR2 activation stimulated lipolysis (see next section on Ketogenesis and ketoacidosis).[20] FFAR2 appears to have very different effects on lipolysis in mice depending on their energy conditions and nutritional status.[9] While SCFAs and FFAR2 have been suggested to stimulate lipolysis in humans on low glucose diets (study described in section on Ketogenesis and ketoacidosis), the role of FFAR2 in this stimulation is unclear and requires further study.[62]

Ketogenesis and ketoacidosis

acidic. This condition, a form of acidosis termed ketoacidosis, is life-threatening.[22] In addition to serving as a tissue nutrient and blood acidifier, one of the circulating ketone bodies appears to have another function: acetoacetic acid activates FFAR2. In a mouse model of starvation-induced ketogenesis: 1) the plasma concentration of acetoacetate was markedly increased in wild-type as well as Ffar2 gene knockout mice while at the same time plasma levels of acetic, propionic, and butyric acids were, as a consequence of starvation, far below those that would activate FFAR2; 2) plasma free fatty acid levels were elevated in wild type but not Ffar2 gene knockout mice; 3) fat tissue weight was significantly higher in Ffar2 gene knockout than wild-type mice; and 4) the lean body masses in the two groups of mice were comparable.[20] These results suggest that in mice the acetoacetic acid-induced activation of FFAR2 on fat cells stimulates lipolysis and thereby the rises in plasma fatty acid levels that occur in mild and severe ketoacidosis. Thus, FFAR2 appears to have a physiological role in mild but a pathological role in severe ketogenesis in mice.[20][62] The acetoacetic acid-FFAR2-lipolysis linkage may occur in humans. Ketogenic diets i.e., low-carbohydrate diets, have been used to treat various neurological diseases. Individuals on these diets develop a mild form of ketogenesis consisting of moderately high blood levels of the ketone bodies and fatty acids. The increased fatty acid levels of individuals on these diets may be due to the stimulation of lipolysis by acetoacetic acid-induced activation of FFAR2 on their fat cells. High blood levels of beta-hydroxybutyric acid may activate hydroxycarboxylic acid receptor 2 on fat cells to similarly cause elevated fatty acid blood levels. Further studies are needed to support this role for FFAR2 in elevating fatty acid blood levels in humans on the ketogenic diet.[62]

Blood pressure regulation and vascular disease

The infusion of a FFAR2-activating SCFA, i.e. acetic, propionic, or butyric acid, into mice causes short-term falls in their blood pressure.

white blood cells of hypertensive individuals was significantly lower than that in individuals with normal blood pressures.[68] These findings suggest that FFAR2 functions to reduce blood pressure as well as hypertension induced vascular disease in mice and humans and support further studies to examine these relationships.[64]

Cancer

Preliminary studies suggest that FFAR2 may be involved in some types of cancer.

A549 lung cancer cells;[72] further studies in A549 as well as H1299 human lung cancer cells found that propionic acid inhibited their stimulated migration, invasiveness, and colony growth in cell culture assays but did not do so in FFAR2 gene knockout A549 or H1299 cells.[71] These results suggest that FFAR2 may inhibit the development and/or progression of human lung cancer.[71][72] (Studies have also reported that SCFAs inhibit the proliferation and caused apoptosis in cultured human breast cancer MCF-7[73] and human bladder cancer NaB cells[74] but neither study determined if their actions involved FFAR2.) Further studies are needed to confirm and broaden these preliminary findings and extend them to other types of cancer.[9][69]

Nervous system

Microglia are the resident immune cells of the central nervous system (i.e., brain and spinal cord). They are key contributors to the development and maintenance of neural tissues[75] and mediate inflammatory responses to, e.g., bacterial invasion as well as the pathological inflammations which underlie many neurological diseases.[13][14] Studies have reported that compared to control mice, germ-free mice (which lack SCFAs in their gastrointestinal tracts) have increased levels of immature microglia throughout their brains; SCFA supplementation normalized the microglial cell maturity. Furthermore, Ffar2 gene knockout mice likewise had increased levels of immature microglia throughout their brains. These studies suggest that FFAR2 is required for the maturation, and therefore functionality, of the microglia in mice.[9][10] Since mouse microglial cells do not express FFAR2, the FFAR2-bearing cells responsible for the maturation and thereby functionality of the mouse's microglia are unclear.[9]

Studies have suggested that promoting the intestinal microbiota's production of SCFAs may suppress the development and/or progression of various human neurological diseases, particularly

strokes, pathological anxiety and depression disorders,[13][14] behavioral and social communication disorders,[77] and postoperative cognitive dysfunction.[78] Some of these studies mention the possibility that SCFA-induced activation of FFAR2 suppresses these diseases and disorders but give no evidence to support this. The studies often do suggest that the SCFAs act by various other mechanisms to achieve their neurological effects.[79] Furthermore, the role of SCFAs in humans with these diseases may be unclear. For example, two extensive reviews found that studies on the role of intestinal SCFAs in multiple sclerosis patients were inconclusive.[80][81] There is a need to define the precise roles of SCFAs, FFAR2, and the other proposed causal factors in these neurological diseases and disorders.[13][76]

Infections

Bacterial infections

Studies have shown that bacterial infections of the human urinary tract, vagina (i.e., bacterial vaginosis), gums (i.e., periodentitis), and abscesses in various tissues are associated with high concentrations of SCFAs, especially acetic acid, at the infection sites or, in urinary tract infections, the urine. These SCFAs may be made and released by the bacteria and/or host cells in the infected areas.[15] Several studies have suggested that SCFAs act through FFAR2 to suppress these infections. 1) Compared to control mice, Ffar2 gene knockout mice had more severe infections in models of Citrobacter rodentium, Klebsiella pneumoniae, Clostridioides difficile,[15] and Streptococcus pneumoniae bacterial infections.[82] 2) Injection of acetic acid into the peritoneum 1/2 hour before or 6 hours after injection of Staphylococcus aureus bacteria into the bloodstream of mice reduced signs of severe disease, the amount of body weight lost, and the numbers of bacteria recovered from the liver, spleen, and kidneys; these reductions did not occur in Fffar2 gene knockdown mice.[83] And, 3) higher circulating blood cell levels of FFAR2 messenger RNA were associated with higher survival rates in patients with sepsis, i.e., disseminated bacterial infections, compared to patients with lower levels of blood cell FFAR2 messenger RNA.[84] These studies suggest that FFAR2 reduces the severity of the cited bacterial infections in humans and mice and recommend further studies on the roles of FFAR2 in these and other bacterial infections.[15]

Viral infections

Mice pretreated for 4 weeks with diets that raised their intestinal SCFAs levels had reduced viral levels and pulmonary inflammation during the course of respiratory syncytial virus infection; these reductions did not occur in Ffar2 gene knockout mice or mice pretreated with antibiotics to reduce their intestines' SCFAs levels. Thus, SCFA activated FFAR2 appeared to reduce the severity of this viruses infection in mice.[15] Different results were found in a study examining influenza A virus's ability to enter and thereby infect human A549 lung cancer cells and mouse 264RAW .7 macrophages. Reduction of FFAR2 using gene knockdown methods reduced the virus's ability to enter into both cell types. Treating A549 cells with FFAR2 agonists, either 4-CMTB or compound 58, also inhibited the virus's entry into these cells. Analysis of this inhibition revealed that Influenza A virus entered these cells by binding to their surface membrane sialic acid receptors; this binding triggered endocytosis, i.e., internalization, of these cells' sialic acid receptors along with their attached viruses. A portion of the sialic acid receptor-bound virus also binds to and activates FFAR 2; this activation increased the endocytosis triggered by the virus's binding to the sialic acid receptors.[16] 4-CMTB and Compound 58 acted to block the ability of the sialic acid-bound virus to enhance endocytosis.[16][18]

FFAR2-FFAR3 receptor heteromer

The FFAR2-FFAR3

monocytes isolated from human blood and macrophages that were differentiated from these monocytes (see monocyte differentiation into macrophages). Like other protein dimers, the FFAR2-FFAR3 protein dimer had activities that differed from each of its FFAR monomer proteins. However, FFAR2-FFAR3 dimers have not yet been associated with specific functions, clinical disorders, or clinical diseases.[85]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000126262 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051314 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading

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