| FFAR1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | FFAR1, FFA1R, GPCR40, GPR40, free fatty acid receptor 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:603820;MGI:2684079;HomoloGene:3876;GeneCards:FFAR1;OMA:FFAR1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Free fatty acid receptor 1 (FFAR1), also known asG-protein coupled receptor 40 (GPR40), is arhodopsin-likeG-protein coupled receptor[5] that is coded (i.e., its synthesis is directed) by theFFAR1gene.[6] This gene is located on the short (i.e., "q") arm ofchromosome 19 at position 13.12 (location notated as 19q13.12).[7] G protein-coupled receptors (also termed GPRs or GPCRs) 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.[5] FFAR1 is a member of a small family of structurally and functionally related GPRs termedfree fatty acid receptors (FFARs). This family includes at least three other FFARsviz.,FFAR2 (also termed GPR43),FFAR3 (also termed GPR41), andFFAR4 (also termed GPR120). FFARs bind and thereby are activated by certainfatty acids.[8]
Studies suggest that FFAR1 may be involved in the development of obesity,type 2 diabetes,[9][10] and various emotional, behavioral, learning, andcognition defects[11] such asAlzheimer's disease.[12] FFAR1 may also be involved in the perception of pain, the tastes of and preferences for eating fatty and sweet foods,[9] the pathological replacement of injured tissue withfibrosis and scarring,[13] and the malignant behavior, i.e.,proliferation,invasiveness, andmetastasis, of some types of cancer cells.[14]
Various fatty acids, including in particular twoomega-3 fatty acids,docosahexaenoic andeicosapentaenoic acids,[11] have been consumed indiets andsupplements for the purposes of preventing or treating the disorders that recent studies suggest are associated with abnormalities in FFAR1's functions. It is now known that these fatty acids activate (i.e. areagonists of) FFAR1 as well as FFAR4. While dietary and supplemental omega-3 fatty acids have had no or only marginally significant therapeutic effects on these disorders (seehealth effects of omega-3 fatty acid supplementation), drugs have been developed that are more potent and selective in activating FFAR1 than the omega-3 fatty acids.[11][15][16] Furthermore, drugs have been developed that potently inhibit (i.e. areantagonists of) FFAR1.[15] This raised the possibility that the drugs may be more effective than the omega-3 fatty acids in treating these diseases and prompted studies testing their effectiveness to do so.[17] These studies, which arepreclinical studies oncultured cells andanimal models of disease plus someclinical studies, are detailed here.
FFARs are activated by specifictypes of fatty acids.[8] FFAR2 and FFAR3 are activated byshort-chain fatty acids (i.e., fatty acid chains consisting of 2 to 5 carbon atoms) such asacetic,butyric, andpropionic acids.[18] FFAR1 and FFAR4 are activated by1)medium-chain fatty acids (i.e., fatty acids consisting of 6-12 carbon atoms) such ascapric andlauric acids;2)long-chain andvery long-chain fatty acids (i.e. fatty acids consisting respectively of 13 to 21 or more than 21 carbon atoms)unsaturated fatty acids such asmyristic andsteric acids;3)long chain monounsaturated fatty acidss such asoleic andpalmitoleic acids;4)long and very long chain polyunsaturated fatty acids such as the omega-3 fatty acidsalpha-linolenic,eicosatrienoic,eicosapentaenoic, and docosahexaenoic acids andomega-6 fatty acids such aslinoleic,gamma-linolenic,dihomo-gamma-linolenic,arachidonic, anddocosatetraenoic acids;[9] and5) theomega hydroxy fatty acid,20-hydroxyeicosatetraenoic acid.[15][19][20] Among the fatty acids that activate FFAR1 (and FFAR4), docosahexaenoic and eicosapentaenoic acids are commonly regarded as the main dietary fatty acids that do so and may be useful therapeutic agents.[11]
The drugs that arefull agonists (i.e., can fully activate) FFAR1 include GW5809 (about 60-fold more potent in activating FFAR1 than FFAR4)[8] and five drugs, AM 1638, AP8, compound 1[15] SCO-267,[21] and T-3601386[22] which have no reports clearly defining their ability to activate FFAR4. The drugs that arepartial agonists (i.e., activate but cannot fully activate) FFAR1 include TAK-875, also termed fasiglifam, which is >1,000 more potent in activating FFAR1 than FFAR4,[8] MK‐8666, which activates FFAR1 and said to be less effective in activating FFAR4,[23] and two drugs, AMG 837T[24] and LY3104607[25] which have no reports clearly defining their ability to activate FFAR4. GW1100[26] and ANT203[27] areantagonist, i.e., inhibit the activation, of FFAR1 but do not inhibit FFAR4[28] and DC260126 which inhibits FFAR1 but its effect on FFAR4 has not been clearly reported.[29] ZLY50 is a newly described selective FFAR1 agonist (>400 more potent in activating FFAR1 than FFAR4) that crosses theblood–brain barrier and therefore may prove useful for inhibiting FFAR1 on cells located in thecentral nervous system, i.e. brain andspinal cord.[30]
Cells commonly express both FFAR1 and FFAR4. The fatty acids which activate these two FFARs, including docosahexaenoic and eicosapentaenoic acids, are about equally potent in activating FFAR1 and FFAR4; they also have diverse FFAR1-independent as well as FFAR4-independentmeans of altering cell functions.[8] Furthermore, most of the studies on FFAR1 agonist drugs have used GW9508, a drug that activates FFAR1 but at higher concentrations also activates FFAR4. Finally, many of the FFAR1 agonists and antagonists have not been defined for their impact on FFAR4 and none of them have been fully evaluated for possible FFAR-independent means of altering cell functions. Accordingly, many FFAR1 studies have not clearly determined if the action(s) of a given fatty acid or drug involves FFAR1, FFAR4, both FFARs, FFAR-independent pathways, or combinations of these function-altering avenues.[9][16] The studies reported here address these issues by focusing on those that included examinations of the effects of FFAR1 and FFAR4 inhibitors by themselves or as blockers of the actions of FFAR1 and FFAR4 and/or included experiments using cells or animals that lacked, under-expressed, or overexpressed FFAR1 or FFAR4.
FFAR1 is highly expressed inpancreasbeta cells which produce and releaseinsulin into the blood; pancreasalpha cells which produce and releaseglucagon, a hormone that increases blood glucose levels;[9]enteroendocrine K,L, andI cells of thegastrointestinal tract which respectively produce and releaseglucagon-like peptide-1,gastric inhibitory peptide, andcholecystokinin which regulate insulin and blood glucose levels;[10]monocytes[9] andM2 macrophages[10] which contribute to regulatingimmune responses such asinflammation;bone modeling cells (i.e.osteoblasts andosteoclasts); and taste receptor-bearing cells in the tongue'staste buds.[9] FFAR1 is also expressed inbone marrow-derived macrophages;[9]neurons in thecentral nervous system, e.g. theolfactory bulb,striatum,hippocampus,midbrain,hypothalamus,cerebellum,cerebral cortex,[31]caudate nucleus[32] and spinal cord;[31] various cell types in thespleen;[33] and various types of cancer cells.[14][33]
Studies to date have implicated FFAR4 but not FFAR1 in the development and remodeling offat tissue and in generating body heat, i.e.,thermogenesis, by thebrown fat component of fat tissue (seeFFAR4) in rodents.[9] Indeed, FRAR1 has not yet been reported to be expressed in the fat tissue of mice or humans.[34]
The following studies have suggested that FFAR1 contributes to the regulation of obesity.1)Ffar1gene knockout mice (i.e., mice made to lackFfar1 genes) became obese when fed a low-fat diet[27] whereas control mice became obese only when fed a high-fat diet.[10]2) The FFAR1 agonist SCO-267 reduced the food intake and body weights in diet-induced obese rats, in rats made diabetic by neonatal treatment withstreptozotocin, and in obese mice but not inFfar1 knockout obese mice.[35]3) Another FFAR1 agonist, T-3601386, likewise reduced the food intake and body weight in obese mice but not inFfar1 gene knockout mice.[22]4)SNP genotyping is used to definesingle-nucleotide polymorphisms in order to detectgermline substitutions of a single nucleotide at specific positions inall the genetic material of an organism. SNP genotyping found three variantFFAR1 gene SNPs in individuals with higher body weights,body mass indexes, and fatty tissue masses than individuals not carrying one of these SNP genes. The SNP gene carriers did not evidence abnormal insulin or pancreatic beta cell functions. This study suggested but did not show that the cited SNP FFAR1 protein variants were dysfunctional.[36] And5) a similar study found another SNP in theFFAR1 gene. This SNP replacedserine withglycine at the 180thamino acid of FFAR1. It and the more common FFAR1 protein it replaces are termed Gly180Ser and Gly180Gly, respectively. Gly180Ser FFAR1 was present in 0.42, 1.8, and 2.60% of non-obese, moderately obese, and severely obese individuals, respectively, and its carriers showed reduced plasma insulin responses to an oral lipid challenge. Studies onHeLa cells (i.e., cells derived from humancervical cancer cells) made to express Gly180Ser FFAR1 usingtransfection methods had significantly lower calcium mobilization responses to oleic acid than Hela cells transfected with Gly180Gly FFAR1. This suggests that Gly180Ser FFAR1 is dysfunctional.[37] Modulation of the nutrient taste-sensing pathways (see below section on Taste) using foods, dietary supplements, or drugs that target FFAR1 (and FFAR4, seeFFAR4-dependent taste perception) may prove useful for treating obesity and obesity-related disorders.[35][38][39]
Studies have suggested that FFAR1 acts to suppress the development and/or pathological effects (e.g. inadequateinsulin secretion) of type 2 diabetes.1) Fatty acid activators of FFAR1/FFAR4 enhanced the glucose-stimulated secretion of insulin from cultured mouse pancreas beta-cells, INS-1 rat beta cells, mouse MIN6 beta cells (these cells like other beta cells make and release insulin but are genetically altered to also make and releaseglucagon,somatostatin, andghrelin[40]), andpancreatic islets isolated from humans. These fatty acid activators did not have this action in the absence of concurrent glucose stimulation.[41]2) The FFAR1 agonist TAK-875 increased the amount of insulin released by glucose-stimulated cultured INS-1 cells and isolated rat pancreatic islets. TAK-875 did not have this action in the absence of concurrent glucose stimulation.[41][42]3) The FFAR1 agonist AMG 837 stimulated mouse MIN6 cells to secrete insulin; it also reduce the rises in plasma glucose occurring inglucose tolerance tests in control but notFfar1 gene knockout mice.[24]4) Other FFAR1 agonist drugs including TUG-424, AM-1638, AM-5262, LY2881835,[34] MK-2305, and ZLY50[30] increased insulin secretion and improved glucose tolerance in mice, enhanced glucose-stimulated insulin secretion in mouse and human cultured pancreatic islet cells, and/or improved glucose levels in diabetic mice.[34]5)Ffar1 gene knockout mice had impaired secretion ofglucagon-like peptide-1 andgastric inhibitory polypeptide into the circulation. These two hormones are secreted fromintestinal L-cells andintestinal K-cells, respectively, when stimulated by dietary glucose or fatty acids and act to promote insulin secretion.[38] And6)Ffar1 gene knockout mice fed a high-fat diet for 11 weeks developed obesity, highfasting blood glucose levels,glucose intolerance, andinsulin resistance; control mice feed the high fat diet did not develop these diabetic-like abnormalities.[41][43] Thus, FFAR1 appears to regulate insulin secretion and blood glucose levels thereby suppressing the development and/or pathological consequences of type 2 diabetes in rodents.[34][41]
A double‐blind (i.e., patients and researchers do not know if the patients are taking a drug orplacebo),parallel studyrandomized 63 patients (mean age 55, ranging from 30 to 65 years old) with type 2 diabetes to take the GPR40 agonist MK‐8666 or a placebo for 14 days. MK-8666-treated patients had fasting blood glucose levels that were well below pre-treatment levels by the last treatment day. Placebo-treated patients showed no changes in their blood glucose levels. Among the MK-866-treated patients, 18 instances of mild to moderate drug‐relatedadverse events (i.e., pain in the back, neck, extremity, and/or abdomen; headache; constipation; nausea; and diarrhea) occurred. However, one patient developed elevations in the blood levels of three liver enzymes,alanine aminotransferase,aspartate aminotransferase andalkaline phosphatase. Elevations in these enzymes' blood levels suggest the presence of liver damage (seeliver function tests). The patient continued to take MK-8666 for the 14 day treatment period; two weeks thereafter these enzymes returned to normal levels. The study concluded that this case may have reflected mild MK-8666-induced liver damage. The sponsor,Merck & Co., terminated further development of MK-8666 due to it having a possibly unfavorablerisk–benefit ratio in type 2 diabetic patients.[23] A study conducted in Japan on 1,222 adults with inadequately controlled (i.e. high blood sugar levels) type 2 diabetes were treated with the highly selective FFAR1 agonist TAK-875 in addition to their in-place treatment regimens for 1 year. Blood sugar levels improved 2 weeks after taking the drug and remained improved throughout the study. However, adverse events that emerged during treatment leading to discontinuance of TAK-875 varied between 2.9% and 9.2% depending on the patients' treatment regimens; the incidence of abnormal liver function tests during the trial varied between 0% and 5.8%, again depending on treatment regimens. Further development of TAK-875 was stopped due to concerns about its possiblehepatotoxicity.[44] A recent review of data from TAK-875 global clinical trials by an independent panel of experts overseeing the clinical development program also had concerns about liver safety.[45] A simulated analysis of these studies suggested that this liver toxicity reflected the inhibition of liverbile acid transporters andmitochondrialelectron transport chain enzymes by TAK-875 and itsglycosylated metabolite, TAK-875-glucose.[46][12] The results of these studies have been regarded asproof of the concept that FFAR1 contributes to the regulation of glucose levels in patients with type 2 diabetes and therefore is a potential target for treating these patients with FFAR1 agonists that do not have significantadverse effects such as hepatotoxicity.[12][23] Recentpreclinical studies are examining other FFAR1 agonists for their liver and other toxicities.[15]
The main detectors and mediators of the five majortaste perception elements viz.,saltiness,sourness,bitterness,sweetness, andumami, are the cell-bound GPRs TAS1R2/TAS1R3, TAS1R1/TAS1R3, and multiple subtypes of TAS2R for sweetness, umami, and bitterness, respectively, and selective cell-boundion channels for saltiness and sourness.[47] However, studies indicate that the taste of substances sometimes involves more than one taste-detecting element. For example, taste of the artificial the sweetenersaccharin appears to be detected by a combination of sweetness and bitterness elements.[47] Cells bearing these taste receptors are on thetongue's upper surface,soft palate, upperesophagus,cheek, andepiglottis (seeTaste buds). FFAR1 and FFAR4 appear to contribute to some types of taste perception in rodents.1)Taste bud cells in the back of rodents' tongues express FFAR1 while cells in theepithelium of their tongues'circumvallate papillae express FFAR4.2)Ffar1 andFfar4 gene knockout mice had diminished taste responses to various fatty acids and a lower preference for consuming these fatty acids.3)Ffar1gene knockdown mice had a reduced intake and preference for sucrose in sucrose preference tests.4) Human tongue taste bud cells contain FFAR4 but inconclusive studies suggest it may lack FFAR1.[9][48] And5) a selective activator of FFAR4, TUG-891, enhanced human's fatty orosensation (i.e., false sensation of taste obtained by tongue stimulation) when added to FFAR4-activating dietary fats but not when added to fat-free mineral oil. This finding suggests that in humans FFAR4 activation enhances but does not directly evoke a sensation of fats.[49] Thus, FFAR1 and FFAR4 appear to mediate fatty acid taste perceptions and FFAR1 appears to mediate sweetness taste perception in rodents; taste bud FFAR4 but not FFAR1 appears to enhance the perception of fatty acids and fatty oils in humans. Further studies are needed to define the presence, locations, and precise roles of FFAR1 and FFAR4 in the various taste perceptions of animals and humans.[9][39][47]
FFAR1 is expressed on the neurons and some other cell types in the olfactory bulb, striatum, hippocampus, midbrain, hypothalamus, cerebellum, cerebral cortex,[31] and caudate nucleus of the brain as well as in the spinal cord.[31] FFAR1-activating fatty acids, particularly docosahexaenoic acid, are thought to play critical roles in neurons by maintaining theirsurface membrane integrity, survival,synaptic functions (synapses are specialize parts of neurons which communicate with other neurons),ion channel functions (e.g. communication between cells), and in suppressing the development of certain central nervous system disorders. However, it is often not clear that docosahexaenoic acid achieves these effects by activating FFAR1.[50] The following studies have implicated FFAR1 in various central nervous system functions and/or disorders.1)Ffar1 gene knockout mice showed abnormally reduced anxiety-like behavior in anxiety-inducing tasks compared to control mice.[51]2)Ffar1 gene knockout female mice had abnormally low anxiety responses, abnormally low locomotor activity, and impaired maternal care behavior (i.e., higher rates of offspring neglect andinfanticide) compared to control female mice.[52][53]3) Obese, diabetic male C57BL6/J mice anddb/db obese, diabetic mice (ananimal disease model) have fear-associated learning and memory impairments as determined in various behavioral tests; GW5908 and docosahexaenoic acid reduced these impairments and GW1100 blocked docosahexaenoic acid's effects on learning and memory.[54]4) GW9508 completely restored the learning and memory of mice that had impaired learning and memory due toscopolamine treatment.[54]5) GW9508 reduced the cognitive deficits in A-beta AD mice (i.e. a mouse model ofAlzheimer's disease); this reduction was blocked by treating the mice with GW1100.[55]6) GW9508 similarly improved learning and memory in A-beta AD mice evaluated with other cognition tests.[56] And7) the highly selective FFAR1 agonist TAK-875 reduced thecognitive impairments that occur in APPswe/PS1dE9 mice (another model of Alzheimer disease).[57] These results suggest that FFAR1 may be, and should be evaluated as, a potentile target for the treatment of brain developmental, emotional,[52][53] and mental impairments such as Alzheimer's disease.[55][57][58]
Studies suggest that FFAR1 is involved innociception, i.e., the perception of pain.1) Oral administration of the FFAR1 agonist ZLY50 (which unlike most drugs crosses from the circulation into the central nervous systems'spinal fluid) reduced the pain responses of mice in three pain tests.[30]2) Injection of the FFAR1 agonist GW9508 into thespinal canal of rats decreased their pain response to spinal nerve ligation and heat; the pain-reducing action of GW9508 on spinal nerve ligation was blocked by the FFAR1 antagonist GW1100 but not the FFAR4 antagonist AH7614.[15][59]3)Ffar1 gene knockout mice as well as mice treated with the FFAR1 inhibitor GW1100 had enhanced pain responses in two pain tests.[9][15]4) And theintracerebroventricular injection (i.e., injection into abrain ventricle) of docosahexaenoic acid or GW9508 reduced the pain responses of mice to painful pressure on a paw and to radiant heat; their effects were blocked by intracerebroventricular injections of GW1100.[60] These studies suggest that FFAR1 is involved in reducing rodent pain perception and recommend testing for its involvement in the perception of pain in humans.[54]
Many studies have suggested that FFAR1 alters the malignant behavior of some types of cultured cancer cells. These malignant behaviors include cultured cancer cellmotility andproliferation which are regarded as being related to theinvasiveness and growth rate, respectively, of cancers in animals and humans.1) GW9508, which activates FFAR1 but at higher concentrations also activates FFAR4, stimulated the motility of mouse LL/2 and rat RLCNR lung cancer cells; treatment of these cells with GW9508 plus GW1100 reduced these cells motility to levels below GW9508-treated and GW9508-untreated LL/2 and RLCNR cells. (In the presence of GW1100, GW9508 is assumed to act through FFAR4 but not FFAR1.)2) GW9508 reduced the motility of A549 human lung cancer cells; GW9508 plus GW1100 treatment of these cells further reduced their motility;FFAR1 gene knockdown A549 cells showed less motility than control A549 cells; and GW9508-treated A549FFAR1 gene knockdown cells had less motility than control or GW9508-treated cells. (GW9508 is assumed to act through FFAR4, not FFAR1, inFFAR1 gene knockdown or GW1100-treated cells.)3) GW9508 did not alter the proliferation of LL/2, RLCNR, or A549 cells but in combination with GW1100 slightly decreased the proliferation of A549 but not LL/2 or RLCNR cells. These three sets of results suggest that FFAR1 enhances while FFAR4 inhibits the motility of LL/2, RLCNR, and A549 cells and that FFAR4 reduces A549 but not LL/2 or RLCNR cell proliferation.[14][61]4) Similar studies using the FFAR4 agonist TUG-891 and eicosapentaenoic acid in control andFFAR4 gene knockdown human DU145 and PC-3 prostate cancer cells suggested that FFA4 promotes these cells motility and proliferation.5) GW9508 inhibited the motility of hamster pancreas cancer HPD1NR cells (which express FFAR1 but not FFAR4), stimulated the motility of hamster pancreas HPD2NR cancer cells (which express FFAR4 but not FFAR1), and slightly inhibited the motility of humanPANC-1 pancreas cancer cells (which express FFAR1 and FFAR4). GW9508 markedly increased the motility of PANC-1 cells when they were also treated with GW1100. These results indicate that FFAR1 inhibits while FFA4 promotes motility in the three types of rodent pancreas cancer cells.[14][62] And6) studies in MG-63 human osteosarcoma (i.e. bone cancer) cells and the far more highly mobile MG63-R7 human osteosacromea cells suggest that FFAR1 inhibits and FFAR4 promotes motility.[14][63] The latter three sets of results indicate that the roles of FFAR1 and FFAR4 in regulating cancer cell motility vary with the types of cancer cells studied.[14][64]) Finally, studies in patients have shown that FFAR1 is overexpressed in someinsulinomas (i.e. cancers derived from pancreas beta cells), in high grade and/or advanced stage ovarian cancers, and in high grade, advanced stage, and/or poor prognosiscolorectal cancers. The overexpression of FFAR1 in these cancers suggests that it may play a role in their development and/or progression,[64]
FFAR1 and FFAR4 are expressed in humanMDA-MB-231,MCF-7, and SK-BR-3 breast cancer cells and appear to regulate some of their and other types of breast cancer cells' malignant behaviors.1) MDA-MB-231 cells that did not expressFFAR1 (due toFFAR1 gene knockdown) or overexpressed FFRA1 (due totransfection with a FFAR1-producingplasmid) had lower and higher proliferation responses, respectively, to the FFAR1/FFAR4 activator, oleic acid, compared to control MDA-MB-231 cells.2)T-47D human breast cancer cells (which express very low levels of FFAR4) and MCF-7 cells transfected with the FFAR-1-producing plasmid had increased proliferative responses to oleic acid compared to control cells.[8][65]3) The highly selective FFAR4 agonist TUG-891 reduced the proliferation of MCF-7 and MDA-MB-231 cells.[66]4) GW9508 increased the motility of FFAR4 knockdown MCF-7 and SK-BR-3 breast cancer cells compared to their respective control (i.e., FFAR4-expressing) MCF7 and SK-BR-3 cells.5) GW9508 increased the development of lung tumors innude mice injected with control MDA-MB-231 cells but did not do so in nude mice injected with FFAR4 knockdown MDA-MB-231 cells.[8][67] These studies suggest that FFAR1 promotes the proliferation but inhibits the motility and FFAR4 promotes the motility and lung metastasis of human breast cancer cells. And6)Clinical studies have reported that FFAR4 levels are higher in certain types of more aggressive human breast cancers and therefore may be a marker of disease severity and a target for treating these cancers (seeFFAR4 in breast cancer). Similar studies on FFAR1 in human breast cancer are needed to determine its medical relevancy.[8]
Recent studies suggest that FFAR1 is involved in pathological tissuefibrosis, i.e., thehealing of tissue injury in whichconnective tissue replaces normaltissue leading to tissue remodeling, the formation of permanentscar tissue, and damaged organs.1)Ffar1 gene knockout mice were protected from developing fibrotic kidneys in three models of this disease (unilateral obstruction of a single kidney'sureter, long-term kidneyischemia due to reducing blood flow to a single kidney, and adenine diet-induced chronic fibrotic kidney disease).2) PBI-4050 (i.e., 3-pentylbenzeneacetic acid sodium salt), a FFAR1 agonist, blocked the development of fibrosis in rodent kidney, liver, heart, lung, pancreas, and skin models of pathological fibrosis.[13]3) In a model ofnon-alcoholic fatty liver disease.Ffar1 gene knockout mice developed less liver inflammation and fibrosis than control mice.[68] And4)topical application of GW5908 to smallskin biopsy-like wounds (also termed punch wounds) in the skin of male mice increased the levels oftype I collagen in the wound tissues; however it also decreased the size of these wounds and increased the speed with which the wounds healed. This last observation suggests that GW5908 can have positive as well as negative effects on the resolution of tissue injury. Note, however, that the role(s) of FFAR1versus FFAR4 in the actions of GW9808 in this study was not defined.[69] Overall, these studies suggest that FFAR1 may be a target for suppressing the development and/or progression of pathological tissue fibrosis.[12]
