Great attention has been placed on the link between metabolism and immune function giving rise to the term “immunometabolism.” It is widely accepted that inflammation and oxidative stress are key processes that underlie metabolic complications during obesity, diabetes, and atherosclerosis. Therefore, identifying the mechanisms and mediators that are involved in the regulation of both inflammation and metabolic homeostasis is of high scientific and therapeutic interest.
Recent Advances:
G protein-coupled receptors (GPCRs) that signal in response to metabolites have emerged as attractive therapeutic targets in inflammatory disease.
Critical Issues and Future Directions:
In this review, we discuss recent findings about the physiological role of the main metabolite-sensing GPCRs, their implication in immunometabolic disorders, their principal endogenous and synthetic ligands, and their potential as drug targets in inflammation and metabolic disease. Antioxid. Redox Signal. 29, 237–256.
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References
1.
AhmedK, TunaruS, and OffermannsS. GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors. Trends Pharmacol Sci, 30: 557–562, 2009.
2.
Alfonzo-MendezMA, Alcantara-HernandezR, and Garcia-SainzJA. Novel structural approaches to study GPCR regulation. Int J Mol Sci, 18: 27, 2016.
3.
Alvarez-CurtoE and MilliganG. Metabolism meets immunity: the role of free fatty acid receptors in the immune system. Biochem Pharmacol, 114: 3–13, 2016.
4.
AngZ and DingJL. GPR41 and GPR43 in Obesity and Inflammation—Protective or Causative?. Front Immunol, 7: 28, 2016.
5.
AngZ, ErJZ, and DingJL. The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes. Sci Rep, 5: 8134, 2015.
6.
ArakiE and NishikawaT. Oxidative stress: a cause and therapeutic target of diabetic complications. J Diabetes Investig, 1: 90–96, 2010.
7.
Audoy-RemusJ, BozoyanL, DumasA, FilaliM, LecoursC, LacroixS, RivestS, TremblayME, and VallieresL. GPR84 deficiency reduces microgliosis, but accelerates dendritic degeneration and cognitive decline in a mouse model of Alzheimer's disease. Brain Behav Immun, 46: 112–120, 2015.
8.
BelikovAV, SchravenB, and SimeoniL. T cells and reactive oxygen species. J Biomed Sci, 22: 85, 2015.
9.
BenyoZ, GilleA, BennettCL, ClausenBE, and OffermannsS. Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells. Mol Pharmacol, 70: 1844–1849, 2006.
BhuniyaD, UmraniD, DaveB, SalunkeD, KukrejaG, GunduJ, NaykodiM, ShaikhNS, ShitoleP, KurhadeS, DeS, MajumdarS, ReddySB, TambeS, ShejulY, ChughA, PalleVP, MookhtiarKA, CullyD, VaccaJ, ChakravartyPK, NargundRP, WrightSD, GrazianoMP, SinghSB, RoyS, and CaiTQ. Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg Med Chem Lett, 21: 3596–3602, 2011.
12.
BjursellM, AdmyreT, GoranssonM, MarleyAE, SmithDM, OscarssonJ, and BohloolyYM. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab, 300: E211–E220, 2011.
13.
BladCC, TangC, and OffermannsS. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov, 11: 603–619, 2012.
14.
BorenJ and WilliamsKJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol, 27: 473–483, 2016.
15.
BriscoeCP, TadayyonM, AndrewsJL, BensonWG, ChambersJK, EilertMM, EllisC, ElshourbagyNA, GoetzAS, MinnickDT, MurdockPR, SaulsHRJr., ShabonU, SpinageLD, StrumJC, SzekeresPG, TanKB, WayJM, IgnarDM, WilsonS, and MuirAI. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem, 278: 11303–11311, 2003.
16.
BrownAJ, GoldsworthySM, BarnesAA, EilertMM, TcheangL, DanielsD, MuirAI, WigglesworthMJ, KinghornI, FraserNJ, PikeNB, StrumJC, SteplewskiKM, MurdockPR, HolderJC, MarshallFH, SzekeresPG, WilsonS, IgnarDM, FoordSM, WiseA, and DowellSJ. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem, 278: 11312–11319, 2003.
17.
CaiTQ, RenN, JinL, ChengK, KashS, ChenR, WrightSD, TaggartAK, and WatersMG. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun, 377: 987–991, 2008.
18.
CannerPL, BergeKG, WengerNK, StamlerJ, FriedmanL, PrineasRJ, and FriedewaldW. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol, 8: 1245–1255, 1986.
19.
CarlsonLA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med, 258: 94–114, 2005.
20.
CartoniC, YasumatsuK, OhkuriT, ShigemuraN, YoshidaR, GodinotN, le CoutreJ, NinomiyaY, and DamakS. Taste preference for fatty acids is mediated by GPR40 and GPR120. J Neurosci, 30: 8376–8382, 2010.
21.
CemerskiS, CantagrelA, Van MeerwijkJPM, and RomagnoliP. Reactive oxygen species differentially affect T cell receptor-signaling pathways. J Biol Chem, 277: 19585–19593, 2002.
22.
CerfME. Beta cell dysfunction and insulin resistance. Front Endocrinol, 4: 37, 2013.
23.
ChawlaA, NguyenKD, and GohYP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol, 11: 738–749, 2011.
CorreaPR, KruglovEA, ThompsonM, LeiteMF, DranoffJA, and NathansonMH. Succinate is a paracrine signal for liver damage. J Hepatol, 47: 262–269, 2007.
26.
DandonaP, AljadaA, and BandyopadhyayA. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol, 25: 4–7, 2004.
27.
DandonaP, ThusuK, CookS, SnyderB, MakowskiJ, ArmstrongD, and NicoteraT. Oxidative damage to DNA in diabetes mellitus. Lancet, 347: 444–445, 1996.
28.
DefossaE and WagnerM. Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus. Bioorg Med Chem Lett, 24: 2991–3000, 2014.
29.
DunbarRL and GelfandJM. Seeing red: flushing out instigators of niacin-associated skin toxicity. J Clin Invest, 120: 2651–2655, 2010.
30.
EdfalkS, StenebergP, and EdlundH. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes, 57: 2280–2287, 2008.
31.
EizirikDL, ColliML, and OrtisF. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol, 5: 219–226, 2009.
32.
El-AshmawyNE, KhedrEG, El-BahrawyHA, and Al-TantawySM. Chemopreventive effect of omega-3 polyunsaturated fatty acids and atorvastatin in rats with bladder cancer. Tumour Biol, 39: 1010428317692254, 2017.
33.
ErreaA, CayetD, MarchettiP, TangC, KluzaJ, OffermannsS, SirardJC, and RumboM. Lactate inhibits the pro-inflammatory response and metabolic reprogramming in murine macrophages in a GPR81-independent manner. PLoS One, 11: e0163694, 2016.
34.
FialaM, KooijG, WagnerK, HammockB, and PellegriniM. Modulation of innate immunity of patients with Alzheimer's disease by omega-3 fatty acids. FASEB J, 31: 3229–3239, 2017.
35.
FitzgeraldK, WhiteS, BorodovskyA, BettencourtBR, StrahsA, ClausenV, WijngaardP, HortonJD, TaubelJ, BrooksA, FernandoC, KauffmanRS, KallendD, VaishnawA, and SimonA. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med, 376: 41–51, 2017.
36.
FredrikssonR, HoglundPJ, GloriamDE, LagerstromMC, and SchiothHB. Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett, 554: 381–388, 2003.
37.
FredrikssonR and SchiothHB. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol, 67: 1414–1425, 2005.
38.
FujiwaraK, MaekawaF, and YadaT. Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab, 289: E670–E677, 2005.
39.
GeH, LiX, WeiszmannJ, WangP, BaribaultH, ChenJL, TianH, and LiY. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology, 149: 4519–4526, 2008.
40.
GeH, WeiszmannJ, ReaganJD, GupteJ, BaribaultH, GyurisT, ChenJL, TianH, and LiY. Elucidation of signaling and functional activities of an orphan GPCR, GPR81. J Lipid Res, 49: 797–803, 2008.
41.
GetherU. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev, 21: 90–113, 2000.
42.
GmünderH, EckHP, BenninghoffB, RothS, and DrogeW. Macrophages regulate intracellular glutathione levels of lymphocytes. Evidence for an immunoregulatory role of cysteine. Cell Immunol, 129: 32–46, 1990.
43.
GracianoMF, ValleMM, KowluruA, CuriR, and CarpinelliAR. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets. Islets, 3: 213–223, 2011.
44.
GranierS and KobilkaB. A new era of GPCR structural and chemical biology. Nat Chem Biol, 8: 670–673, 2012.
45.
HakakY, Lehmann-BruinsmaK, PhillipsS, LeT, LiawC, ConnollyDT, and BehanDP. The role of the GPR91 ligand succinate in hematopoiesis. J Leukoc Biol, 85: 837–843, 2009.
46.
HamelD, SanchezM, DuhamelF, RoyO, HonoreJC, NoueihedB, ZhouT, Nadeau-ValleeM, HouX, LavoieJC, MitchellG, MamerOA, and ChemtobS. G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery. Arterioscler Thromb Vasc Biol, 34: 285–293, 2014.
47.
HanefeldM, PistroschF, BornsteinSR, and BirkenfeldAL. The metabolic vascular syndrome - guide to an individualized treatment. Rev Endocr Metab Disord, 17: 5–17, 2016.
48.
HansonJ, GilleA, ZwykielS, LukasovaM, ClausenBE, AhmedK, TunaruS, WirthA, and OffermannsS. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest, 120: 2910–2919, 2010.
49.
HaraT, HirasawaA, IchimuraA, KimuraI, and TsujimotoG. Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. J Pharm Sci, 100: 3594–3601, 2011.
50.
HeW, MiaoFJ, LinDC, SchwandnerRT, WangZ, GaoJ, ChenJL, TianH, and LingL. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature, 429: 188–193, 2004.
51.
HirasawaA, TsumayaK, AwajiT, KatsumaS, AdachiT, YamadaM, SugimotoY, MiyazakiS, and TsujimotoG. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med, 11: 90–94, 2005.
52.
HongYH, NishimuraY, HishikawaD, TsuzukiH, MiyaharaH, GotohC, ChoiKC, FengDD, ChenC, LeeHG, KatohK, RohSG, and SasakiS. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology, 146: 5092–5099, 2005.
53.
HoqueR, FarooqA, GhaniA, GorelickF, and MehalWZ. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology, 146: 1763–1774, 2014.
54.
HotamisligilGS. Inflammation and metabolic disorders. Nature, 444: 860–867, 2006.
55.
HotamisligilGS, ShargillNS, and SpiegelmanBM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 259: 87–91, 1993.
56.
HuangW, GuoHL, DengX, ZhuTT, XiongJF, XuYH, and XuY. Short-Chain Fatty Acids Inhibit Oxidative Stress and Inflammation in Mesangial Cells Induced by High Glucose and Lipopolysaccharide. Exp Clin Endocrinol Diabetes, 125: 98–105, 2017.
57.
HustedAS, TrauelsenM, RudenkoO, HjorthSA, and SchwartzTW. GPCR-Mediated Signaling of Metabolites. Cell Metab, 25: 777–796, 2017.
58.
IchimuraA, HirasawaA, Poulain-GodefroyO, BonnefondA, HaraT, YengoL, KimuraI, LeloireA, LiuN, IidaK, ChoquetH, BesnardP, LecoeurC, VivequinS, AyukawaK, TakeuchiM, OzawaK, TauberM, MaffeisC, MorandiA, BuzzettiR, ElliottP, PoutaA, JarvelinMR, KornerA, KiessW, PigeyreM, CaiazzoR, Van HulW, Van GaalL, HorberF, BalkauB, Levy-MarchalC, RouskasK, KouvatsiA, HebebrandJ, HinneyA, ScheragA, PattouF, MeyreD, KoshimizuTA, WolowczukI, TsujimotoG, and FroguelP. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature, 483: 350–354, 2012.
59.
Irukayama-TomobeY, TanakaH, YokomizoT, Hashidate-YoshidaT, YanagisawaM, and SakuraiT. Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B. Proc Natl Acad Sci U S A, 106: 3930–3934, 2009.
JacksonMJ, PapaS, BolanosJ, BruckdorferR, CarlsenH, ElliottRM, FlierJ, GriffithsHR, HealesS, HolstB, LorussoM, LundE, Oivind MoskaugJ, MoserU, Di PaolaM, PolidoriMC, SignorileA, StahlW, Vina-RibesJ, and AstleySB. Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial function. Mol Aspects Med, 23: 209–285, 2002.
62.
KakuK, ArakiT, and YoshinakaR. Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care, 36: 245–250, 2013.
63.
KalupahanaNS, Moustaid-MoussaN, and ClaycombeKJ. Immunity as a link between obesity and insulin resistance. Mol Aspects Med, 33: 26–34, 2012.
64.
KampME, ShimR, NichollsAJ, OliveiraAC, MasonLJ, BingeL, MackayCR, and WongCH. G Protein-Coupled Receptor 43 Modulates Neutrophil Recruitment during Acute Inflammation. PLoS One, 11: e0163750, 2016.
65.
KarakiS, MitsuiR, HayashiH, KatoI, SugiyaH, IwanagaT, FurnessJB, and KuwaharaA. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res, 324: 353–360, 2006.
66.
KarakiS, TazoeH, HayashiH, KashiwabaraH, TooyamaK, SuzukiY, and KuwaharaA. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol, 39: 135–142, 2008.
67.
KarkiP, KuriharaT, NakamachiT, WatanabeJ, AsadaT, OyoshiT, ShiodaS, YoshimuraM, AritaK, and MiyataA. Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40. Mol Pain, 11: 6, 2015.
68.
KayamaY, RaazU, JaggerA, AdamM, SchellingerIN, SakamotoM, SuzukiH, ToyamaK, SpinJM, and TsaoPS. Diabetic cardiovascular disease induced by oxidative stress. Int J Mol Sci, 16: 25234–25263, 2015.
69.
KeaneKN, CruzatVF, CarlessiR, de BittencourtPIJr., and NewsholmeP. Molecular events linking oxidative stress and inflammation to insulin resistance and beta-cell dysfunction. Oxid Med Cell Longev, 2015: 181643, 2015.
70.
KeaneyJFJr., LarsonMG, VasanRS, WilsonPW, LipinskaI, CoreyD, MassaroJM, SutherlandP, VitaJA, and BenjaminEJ. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol, 23: 434–439, 2003.
71.
KellyAS, RyderJR, MarlattKL, RudserKD, JenkinsT, and IngeTH. Changes in inflammation, oxidative stress and adipokines following bariatric surgery among adolescents with severe obesity. Int J Obes (Lond), 40: 275–280, 2016.
72.
KellyB and O'NeillLA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res, 25: 771–784, 2015.
73.
KimMH, KangSG, ParkJH, YanagisawaM, and KimCH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology, 145: 396–406.e1-10, 2013.
74.
KimS, HwangJ, XuanJ, JungYH, ChaHS, and KimKH. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLoS One, 9: e97501, 2014.
75.
KimS, KimJH, ParkBO, and KwakYS. Perspectives on the therapeutic potential of short-chain fatty acid receptors. BMB Rep, 47: 173–178, 2014.
76.
KimuraI, OzawaK, InoueD, ImamuraT, KimuraK, MaedaT, TerasawaK, KashiharaD, HiranoK, TaniT, TakahashiT, MiyauchiS, ShioiG, InoueH, and TsujimotoG. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun, 4: 1829, 2013.
77.
KnowlesHJ, te PoeleRH, WorkmanP, and HarrisAL. Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways. Biochem Pharmacol, 71: 646–656, 2006.
78.
KowaltowskiAJ, de Souza-PintoNC, CastilhoRF, and VercesiAE. Mitochondria and reactive oxygen species. Free Radic Biol Med, 47: 333–343, 2009.
79.
KristinssonH, BergstenP, and SargsyanE. Free fatty acid receptor 1 (FFAR1/GPR40) signaling affects insulin secretion by enhancing mitochondrial respiration during palmitate exposure. Biochim Biophys Acta, 1853: 3248–3257, 2015.
80.
KumarP, NatarajanK, and ShanmugamN. High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. Cell Signal, 26: 528–539, 2014.
81.
LanH, HoosLM, LiuL, TetzloffG, HuW, AbbondanzoSJ, VassilevaG, GustafsonEL, HedrickJA, and DavisHR. Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease. Diabetes, 57: 2999–3006, 2008.
82.
LandrayMJ, HaynesR, HopewellJC, ParishS, AungT, TomsonJ, WallendszusK, CraigM, JiangL, CollinsR, and ArmitageJ. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 371: 203–212, 2014.
83.
LauringB, TaggartAK, TataJR, DunbarR, CaroL, ChengK, ChinJ, CollettiSL, CoteJ, KhaliliehS, LiuJ, LuoWL, MacleanAA, PetersonLB, PolisAB, SirahW, WuTJ, LiuX, JinL, WuK, BoatmanPD, SempleG, BehanDP, ConnollyDT, LaiE, WagnerJA, WrightSD, CuffieC, MitchelYB, RaderDJ, PaoliniJF, WatersMG, and PlumpA. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med, 4: 148ra115, 2012.
84.
Le PoulE, LoisonC, StruyfS, SpringaelJY, LannoyV, DecobecqME, BrezillonS, DupriezV, VassartG, Van DammeJ, ParmentierM, and DetheuxM. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem, 278: 25481–25489, 2003.
85.
LeeSU, InHJ, KwonMS, ParkBO, JoM, KimMO, ChoS, LeeS, LeeHJ, KwakYS, and KimS. beta-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-kappaB. Biol Pharm Bull, 36: 1754–1759, 2013.
86.
LeifkeE, NaikH, WuJ, ViswanathanP, DemannoD, KipnesM, and VakilynejadM. A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin Pharmacol Ther, 92: 29–39, 2012.
87.
LerchMM, ConwellDL, and MayerleJ. The anti-inflammasome effect of lactate and the lactate GPR81-receptor in pancreatic and liver inflammation. Gastroenterology, 146: 1602–1605, 2014.
88.
LiYH, ChoiDH, LeeEH, SeoSR, LeeS, and ChoEH. Sirtuin 3 (SIRT3) Regulates alpha-Smooth Muscle Actin (alpha-SMA) Production through the succinate dehydrogenase-G protein-coupled receptor 91 (GPR91) pathway in hepatic stellate cells. J Biol Chem, 291: 10277–10292, 2016.
89.
LiZ, QiuQ, GengX, YangJ, HuangW, and QianH. Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development. Expert Opin Investig Drugs, 25: 871–890, 2016.
90.
Littlewood-EvansA, SarretS, ApfelV, LoesleP, DawsonJ, ZhangJ, MullerA, TiganiB, KneuerR, PatelS, ValeauxS, GommermannN, Rubic-SchneiderT, JuntT, and CarballidoJM. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med, 213: 1655–1662, 2016.
91.
LiuHD, WangWB, XuZG, LiuCH, HeDF, DuLP, LiMY, YuX, and SunJP. FFA4 receptor (GPR120): a hot target for the development of anti-diabetic therapies. Eur J Pharmacol, 763: 160–168, 2015.
92.
LiuQ, ShimoyamaT, SuzukiK, UmedaT, NakajiS, and SugawaraK. Effect of sodium butyrate on reactive oxygen species generation by human neutrophils. Scand J Gastroenterol, 36: 744–750, 2001.
93.
LiuR, van VeldhovenJP, and APIJ. The role of the C-terminus of the human hydroxycarboxylic acid receptors 2 and 3 in G protein activation using Galpha-engineered yeast cells. Eur J Pharmacol, 770: 70–77, 2016.
94.
LiuY, ZhangQ, ChenLH, YangH, LuW, XieX, and NanFJ. Design and synthesis of 2-alkylpyrimidine-4,6-diol and 6-alkylpyridine-2,4-diol as potent GPR84 agonists. ACS Med Chem Lett, 7: 579–583, 2016.
95.
Lorente-CebrianS, CostaAG, Navas-CarreteroS, ZabalaM, LaiglesiaLM, MartinezJA, and Moreno-AliagaMJ. An update on the role of omega-3 fatty acids on inflammatory and degenerative diseases. J Physiol Biochem, 71: 341–349, 2015.
96.
LukasovaM, MalavalC, GilleA, KeroJ, and OffermannsS. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest, 121: 1163–1173, 2011.
97.
MaD, TaoB, WarashinaS, KotaniS, LuL, KaplamadzhievDB, MoriY, TonchevAB, and YamashimaT. Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci Res, 58: 394–401, 2007.
98.
ManciniAD and PoitoutV. GPR40 agonists for the treatment of type 2 diabetes: life after ‘TAKing’ a hit. Diabetes Obes Metab, 17: 622–629, 2015.
99.
MandrikaI, PetrovskaR, and KlovinsJ. Evidence for constitutive dimerization of niacin receptor subtypes. Biochem Biophys Res Commun, 395: 281–287, 2010.
100.
ManosalvaC, MenaJ, VelasquezZ, ColensoCK, BrauchiS, BurgosRA, and HidalgoMA. Cloning, identification and functional characterization of bovine free fatty acid receptor-1 (FFAR1/GPR40) in neutrophils. PLoS One, 10: e0119715, 2015.
101.
MartnerA, AureliusJ, RydstromA, HellstrandK, and ThorenFB. Redox remodeling by dendritic cells protects antigen-specific T cells against oxidative stress. J Immunol, 187: 6243–6248, 2011.
102.
MaslowskiKM and MackayCR. Diet, gut microbiota and immune responses. Nat Immunol, 12: 5–9, 2011.
103.
MaslowskiKM, VieiraAT, NgA, KranichJ, SierroF, YuD, SchilterHC, RolphMS, MackayF, ArtisD, XavierRJ, TeixeiraMM, and MackayCR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature, 461: 1282–1286, 2009.
104.
MathisD and ShoelsonSE. Immunometabolism: an emerging frontier. Nat Rev Immunol, 11: 81, 2011.
105.
McNelisJC, LeeYS, MayoralR, van der KantR, JohnsonAM, WollamJ, and OlefskyJM. GPR43 potentiates beta-cell function in obesity. Diabetes, 64: 3203–3217, 2015.
106.
MilliganG, ShimpukadeB, UlvenT, and HudsonBD. Complex pharmacology of free fatty acid receptors. Chem Rev, 117: 67–110, 2017.
107.
MillsE and O'NeillLA. Succinate: a metabolic signal in inflammation. Trends Cell Biol, 24: 313–320, 2014.
108.
MiyamotoJ, HasegawaS, KasubuchiM, IchimuraA, NakajimaA, and KimuraI. Nutritional Signaling via Free Fatty Acid Receptors. Int J Mol Sci, 17: 450, 2016.
109.
MoniriNH. Free-fatty acid receptor-4 (GPR120): cellular and molecular function and its role in metabolic disorders. Biochem Pharmacol, 110–111: 1–15, 2016.
110.
NadeemA, AhmadSF, Al-HarbiNO, El-SherbeenyAM, Al-HarbiMM, and AlmukhlafiTS. GPR43 activation enhances psoriasis-like inflammation through epidermal upregulation of IL-6 and dual oxidase 2 signaling in a murine model. Cell Signal, 33: 59–68, 2017.
111.
NagasumiK, EsakiR, IwachidowK, YasuharaY, OgiK, TanakaH, NakataM, YanoT, ShimakawaK, TaketomiS, TakeuchiK, OdakaH, and KaishoY. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes, 58: 1067–1076, 2009.
112.
NakamotoK, AizawaF, NishinakaT, and TokuyamaS. Regulation of prohormone convertase 2 protein expression via GPR40/FFA1 in the hypothalamus. Eur J Pharmacol, 762: 459–463, 2015.
113.
NakamotoK, NishinakaT, MatsumotoK, KasuyaF, MankuraM, KoyamaY, and TokuyamaS. Involvement of the long-chain fatty acid receptor GPR40 as a novel pain regulatory system. Brain Res, 1432: 74–83, 2012.
114.
NakamotoK, NishinakaT, SatoN, MankuraM, KoyamaY, KasuyaF, and TokuyamaS. Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain. PLoS One, 8: e81563, 2013.
115.
NakaoS, MoriyaY, FuruyamaS, NiedermanR, and SugiyaH. Propionic acid stimulates superoxide generation in human neutrophils. Cell Biol Int, 22: 331–337, 1998.
116.
NatalicchioA, LabarbutaR, TortosaF, BiondiG, MarranoN, PeschecheraA, CarchiaE, OrlandoMR, LeonardiniA, CignarelliA, MarchettiP, PerriniS, LaviolaL, and GiorginoF. Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway. Diabetologia, 56: 2456–2466, 2013.
117.
NewsholmeP, CruzatVF, KeaneKN, CarlessiR, and de BittencourtPIJr.Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem J, 473: 4527–4550, 2016.
118.
NicolLS, DawesJM, La RussaF, DidangelosA, ClarkAK, GentryC, GristJ, DaviesJB, MalcangioM, and McMahonSB. The role of G-protein receptor 84 in experimental neuropathic pain. J Neurosci, 35: 8959–8969, 2015.
119.
NilssonNE, KotarskyK, OwmanC, and OldeB. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun, 303: 1047–1052, 2003.
120.
O'NeillLA and PearceEJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med, 213: 15–23, 2016.
121.
O'NeillS and O'DriscollL. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev, 16: 1–12, 2015.
122.
OdegaardJI and ChawlaA. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med, 2: a007724, 2012.
123.
OffermannsS. It ain't over ‘til the fat lady sings. Sci Transl Med, 4: 148fs30, 2012.
OffermannsS, CollettiSL, LovenbergTW, SempleG, WiseA, and IJzermanAP. International union of basic and clinical pharmacology. LXXXII: nomenclature and classification of hydroxy-carboxylic acid receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev, 63: 269–290, 2011.
126.
OhDY, TalukdarS, BaeEJ, ImamuraT, MorinagaH, FanW, LiP, LuWJ, WatkinsSM, and OlefskyJM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell, 142: 687–698, 2010.
127.
Organization TWH. 2016. Obesity and overweight. www.who.int/mediacentre/factsheets/fs311/en (accessed December21, 2017).
128.
OuchiN, ParkerJL, LugusJJ, and WalshK. Adipokines in inflammation and metabolic disease. Nat Rev Immunol, 11: 85–97, 2011.
129.
PaerregaardSI, AgerholmM, SerupAK, MaT, KiensB, MadsenL, KristiansenK, and JensenBA. FFAR4 (GPR120) signaling is not required for anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids. Mediat Inflamm, 2016: 1536047, 2016.
130.
PattersonCC, DahlquistGG, GyurusE, GreenA, and SolteszG. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet, 373: 2027–2033, 2009.
131.
PotterM, NewportE, and MortenKJ. The Warburg effect: 80 years on. Biochem Soc Trans, 44: 1499–1505, 2016.
132.
QuinnMT and GaussKA. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol, 76: 760–781, 2004.
133.
RainsJL and JainSK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med, 50: 567–575, 2011.
134.
RamalingamL, MenikdiwelaK, LeMieuxM, DufourJM, KaurG, KalupahanaN, and Moustaid-MoussaN. The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance. Biochim Biophys Acta, 1863: 1106–1114, 2016.
135.
RegardJB, SatoIT, and CoughlinSR. Anatomical profiling of G protein-coupled receptor expression. Cell, 135: 561–571, 2008.
136.
RubicT, LametschwandtnerG, JostS, HintereggerS, KundJ, Carballido-PerrigN, SchwarzlerC, JuntT, VosholH, MeingassnerJG, MaoX, WernerG, RotA, and CarballidoJM. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol, 9: 1261–1269, 2008.
137.
RubicT, TrottmannM, and LorenzRL. Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin. Biochem Pharmacol, 67: 411–419, 2004.
138.
SamuelBS, ShaitoA, MotoikeT, ReyFE, BackhedF, ManchesterJK, HammerRE, WilliamsSC, CrowleyJ, YanagisawaM, and GordonJI. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A, 105: 16767–16772, 2008.
139.
SandovalA, TrivinosF, SanhuezaA, CarrettaD, HidalgoMA, HanckeJL, and BurgosRA. Propionate induces pH(i) changes through calcium flux, ERK1/2, p38, and PKC in bovine neutrophils. Vet Immunol Immunopathol, 115: 286–298, 2007.
140.
SapiehaP, SirinyanM, HamelD, ZanioloK, JoyalJS, ChoJH, HonoreJC, Kermorvant-DucheminE, VarmaDR, TremblayS, LeducM, RihakovaL, HardyP, KleinWH, MuX, MamerO, LachapelleP, Di PoloA, BeausejourC, AndelfingerG, MitchellG, SennlaubF, and ChemtobS. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med, 14: 1067–1076, 2008.
141.
SartoriusT, DrescherA, PanseM, LastovickaP, PeterA, WeigertC, KostenisE, UllrichS, and HaringHU. Mice lacking free fatty acid receptor 1 (GPR40/FFAR1) are protected against conjugated linoleic acid-induced fatty liver but develop inflammation and insulin resistance in the brain. Cell Physiol Biochem, 35: 2272–2284, 2015.
142.
SawzdargoM, GeorgeSR, NguyenT, XuS, KolakowskiLF, and O'DowdBF. A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem Biophys Res Commun, 239: 543–547, 1997.
143.
SchenkS, SaberiM, and OlefskyJM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest, 118: 2992–3002, 2008.
SekiguchiH, KasubuchiM, HasegawaS, PelischN, KimuraI, and IchimuraA. A novel antidiabetic therapy: free fatty acid receptors as potential drug target. Curr Diabetes Rev, 11: 107–115, 2015.
146.
SengaT, IwamotoS, YoshidaT, YokotaT, AdachiK, AzumaE, HamaguchiM, and IwamotoT. LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101: 1185–1187, 2003.
147.
ShenX, YangL, YanS, WeiW, LiangL, ZhengH, and CaiX. The effect of FFAR1 on pioglitazone-mediated attenuation of palmitic acid-induced oxidative stress and apoptosis in betaTC6 cells. Metabolism, 63: 335–351, 2014.
148.
ShiG, SunC, GuW, YangM, ZhangX, ZhaiN, LuY, ZhangZ, ShouP, and NingG. Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling. J Mol Endocrinol, 53: 367–380, 2014.
149.
ShoelsonSE, HerreroL, and NaazA. Obesity, inflammation, and insulin resistance. Gastroenterology, 132: 2169–2180, 2007.
150.
SinaC, GavrilovaO, ForsterM, TillA, DererS, HildebrandF, RaabeB, ChalarisA, SchellerJ, RehmannA, FrankeA, OttS, HaslerR, NikolausS, FolschUR, Rose-JohnS, JiangHP, LiJ, SchreiberS, and RosenstielP. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol, 183: 7514–7522, 2009.
151.
SinghN, GuravA, SivaprakasamS, BradyE, PadiaR, ShiH, ThangarajuM, PrasadPD, ManicassamyS, MunnDH, LeeJR, OffermannsS, and GanapathyV. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity, 40: 128–139, 2014.
152.
SivaprakasamS, PrasadPD, and SinghN. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther, 164: 144–151, 2016.
153.
SleethML, ThompsonEL, FordHE, Zac-VargheseSE, and FrostG. Free fatty acid receptor 2 and nutrient sensing: a proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutr Res Rev, 23: 135–145, 2010.
154.
SogaT, KamoharaM, TakasakiJ, MatsumotoS, SaitoT, OhishiT, HiyamaH, MatsuoA, MatsushimeH, and FuruichiK. Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun, 303: 364–369, 2003.
155.
StenebergP, RubinsN, Bartoov-ShifmanR, WalkerMD, and EdlundH. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab, 1: 245–258, 2005.
156.
StockertJA and DeviLA. Advancements in therapeutically targeting orphan GPCRs. Front Pharmacol, 6: 100, 2015.
157.
StoneVM, DhayalS, BrocklehurstKJ, LenaghanC, Sorhede WinzellM, HammarM, XuX, SmithDM, and MorganNG. GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia, 57: 1182–1191, 2014.
158.
SunP, WangT, ZhouY, LiuH, JiangH, ZhuW, and WangH. DC260126: a small-molecule antagonist of GPR40 that protects against pancreatic beta-Cells dysfunction in db/db mice. PLoS One, 8: e66744, 2013.
159.
SuzukiM, TakaishiS, NagasakiM, OnozawaY, IinoI, MaedaH, KomaiT, and OdaT. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J Biol Chem, 288: 10684–10691, 2013.
160.
TanJ, McKenzieC, PotamitisM, ThorburnAN, MackayCR, and MaciaL. The role of short-chain fatty acids in health and disease. Adv Immunol, 121: 91–119, 2014.
161.
TangH, LuJY, ZhengX, YangY, and ReaganJD. The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun, 375: 562–565, 2008.
162.
TannahillGM, CurtisAM, AdamikJ, Palsson-McDermottEM, McGettrickAF, GoelG, FrezzaC, BernardNJ, KellyB, FoleyNH, ZhengL, GardetA, TongZ, JanySS, CorrSC, HaneklausM, CaffreyBE, PierceK, WalmsleyS, BeasleyFC, CumminsE, NizetV, WhyteM, TaylorCT, LinH, MastersSL, GottliebE, KellyVP, ClishC, AuronPE, XavierRJ, and O'NeillLA. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature, 496: 238–242, 2013.
163.
TazoeH, OtomoY, KarakiS, KatoI, FukamiY, TerasakiM, and KuwaharaA. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res, 30: 149–156, 2009.
164.
TolhurstG, HeffronH, LamYS, ParkerHE, HabibAM, DiakogiannakiE, CameronJ, GrosseJ, ReimannF, and GribbleFM. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes, 61: 364–371, 2012.
165.
TrebatickaJ, DukatA, DurackovaZ, and MuchovaJ. Cardiovascular diseases, depression disorders and potential effects of omega-3 fatty acids. Physiol Res, 66: 363–382, 2017.
166.
TrompetteA, GollwitzerES, YadavaK, SichelstielAK, SprengerN, Ngom-BruC, BlanchardC, JuntT, NicodLP, HarrisNL, and MarslandBJ. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med, 20: 159–166, 2014.
167.
TunaruS, KeroJ, SchaubA, WufkaC, BlaukatA, PfefferK, and OffermannsS. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med, 9: 352–355, 2003.
168.
UronisJM, MuhlbauerM, HerfarthHH, RubinasTC, JonesGS, and JobinC. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One, 4: e6026, 2009.
169.
VangavetiV, ShashidharV, JarrodG, BauneBT, and KennedyRL. Free fatty acid receptors: emerging targets for treatment of diabetes and its complications. Ther Adv Endocrinol Metab, 1: 165–175, 2010.
170.
VenkatakrishnanAJ, DeupiX, LebonG, TateCG, SchertlerGF, and BabuMM. Molecular signatures of G-protein-coupled receptors. Nature, 494: 185–194, 2013.
171.
VenkataramanC and KuoF. The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol Lett, 101: 144–153, 2005.
172.
VerdileG, KeaneKN, CruzatVF, MedicS, SabaleM, RowlesJ, WijesekaraN, MartinsRN, FraserPE, and NewsholmeP. Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer's disease. Mediat Inflamm, 2015: 105828, 2015.
173.
VermaMK, SadasivuniMK, YateeshAN, NeelimaK, MrudulaS, ReddyM, SmithaR, BiswasS, ChandravanshiB, PallaviPM, OommenAM, JagannathMR, and SomeshBB. Activation of GPR40 attenuates chronic inflammation induced impact on pancreatic beta-cells health and function. BMC Cell Biol, 15: 24, 2014.
174.
VinoloMA, HatanakaE, LambertucciRH, NewsholmeP, and CuriR. Effects of short chain fatty acids on effector mechanisms of neutrophils. Cell Biochem Funct, 27: 48–55, 2009.
175.
ViolinJD, CrombieAL, SoergelDG, and LarkMW. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci, 35: 308–316, 2014.
176.
WangJ, WuX, SimonaviciusN, TianH, and LingL. Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem, 281: 34457–34464, 2006.
177.
WellenKE and HotamisligilGS. Inflammation, stress, and diabetes. J Clin Invest, 115: 1111–1119, 2005.
178.
WiseA, FoordSM, FraserNJ, BarnesAA, ElshourbagyN, EilertM, IgnarDM, MurdockPR, SteplewskiK, GreenA, BrownAJ, DowellSJ, SzekeresPG, HassallDG, MarshallFH, WilsonS, and PikeNB. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem, 278: 9869–9874, 2003.
179.
WittenbergerT, SchallerHC, and HellebrandS. An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J Mol Biol, 307: 799–813, 2001.
180.
WuJ, SunP, ZhangX, LiuH, JiangH, ZhuW, and WangH. Inhibition of GPR40 protects MIN6 beta cells from palmitate-induced ER stress and apoptosis. J Cell Biochem, 113: 1152–1158, 2012.
181.
WuP, YangL, and ShenX. The relationship between GPR40 and lipotoxicity of the pancreatic beta-cells as well as the effect of pioglitazone. Biochem Biophys Res Commun, 403: 36–39, 2010.
182.
XiongY, MiyamotoN, ShibataK, ValasekMA, MotoikeT, KedzierskiRM, and YanagisawaM. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci U S A, 101: 1045–1050, 2004.
183.
YinH, ChuA, LiW, WangB, SheltonF, OteroF, NguyenDG, CaldwellJS, and ChenYA. Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328–12338, 2009.
184.
YonezawaT, KurataR, YoshidaK, MurayamaMA, CuiX, and HasegawaA. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr Med Chem, 20: 3855–3871, 2013.
185.
YounJY, SiuKL, LobHE, ItaniH, HarrisonDG, and CaiH. Role of vascular oxidative stress in obesity and metabolic syndrome. Diabetes, 63: 2344–2355, 2014.
186.
YousefiS, CooperPR, PotterSL, MueckB, and JaraiG. Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes. J Leukoc Biol, 69: 1045–1052, 2001.
187.
ZaibiMS, StockerCJ, O'DowdJ, DaviesA, BellahceneM, CawthorneMA, BrownAJ, SmithDM, and ArchJR. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett, 584: 2381–2386, 2010.
188.
Zandi-NejadK, TakakuraA, JurewiczM, ChandrakerAK, OffermannsS, MountD, and AbdiR. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J, 27: 4366–4374, 2013.
189.
ZhangJH, FerranteA, ArrigoAP, and DayerJM. Neutrophil stimulation and priming by direct contact with activated human T lymphocytes. J Immunol, 148: 177–181, 1992.
190.
ZhangQ, YangH, LiJ, and XieX. Discovery and characterization of a novel small-molecule agonist for medium-chain free fatty acid receptor G protein-coupled receptor 84. J Pharmacol Exp Ther, 357: 337–344, 2016.
191.
ZhaoJ, WangH, ShiP, WangW, and SunY. GPR120, a potential therapeutic target for experimental colitis in IL-10 deficient mice. Oncotarget, 8: 8397–8405, 2017.
192.
ZuoL, ZhouT, PannellBK, ZieglerAC, and BestTM. Biological and physiological role of reactive oxygen species—the good, the bad and the ugly. Acta Physiol (Oxf), 214: 329–348, 2015.
