SUCNR1

SUCNR1 is expressed by human:{{cite journal | vauthors = Li X, Xie L, Qu X, Zhao B, Fu W, Wu B, Wu J | title = GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses | journal = FASEB Journal| volume = 34 | issue = 10 | pages = 13091–13105 | date = October 2020 | pmid = 32812686 | doi = 10.1096/fj.202001037R | doi-access = free | url = }} a) hepatic stellate cells (i.e., pericytes found in the perisinusoidal space of the liver);{{cite journal | vauthors = Li YH, Woo SH, Choi DH, Cho EH | title = Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells | journal = Biochemical and Biophysical Research Communications | volume = 463 | issue = 4 | pages = 853–8 | date = August 2015 | pmid = 26051274 | doi = 10.1016/j.bbrc.2015.06.023 | url = }}{{cite journal | vauthors = de Castro Fonseca M, Aguiar CJ, da Rocha Franco JA, Gingold RN, Leite MF | title = GPR91: expanding the frontiers of Krebs cycle intermediates | journal = Cell Communication and Signaling | volume = 14 | issue = | pages = 3 | date = January 2016 | pmid = 26759054 | pmc = 4709936 | doi = 10.1186/s12964-016-0126-1 | doi-access = free | url = }}{{cite journal | vauthors = Chen H, Jin C, Xie L, Wu J | title = Succinate as a signaling molecule in the mediation of liver diseases | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1870 | issue = 2 | pages = 166935 | date = February 2024 | pmid = 37976628 | doi = 10.1016/j.bbadis.2023.166935 | s2cid = 265270839 | url = | doi-access = free }} b) neutrophils,{{cite journal | vauthors = Nunns GR, Vigneshwar N, Kelher MR, Stettler GR, Gera L, Reisz JA, D'Alessandro A, Ryon J, Hansen KC, Gamboni F, Moore EE, Peltz ED, Cohen MJ, Jones KL, Sauaia A, Liang X, Banerjee A, Ghasabyan A, Chandler JG, Rodawig S, Jones C, Eitel A, Hom P, Silliman CC | title = Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS | journal = Annals of Surgery | volume = 276 | issue = 6 | pages = e944–e954 | date = December 2022 | pmid = 33214479 | pmc = 8128932 | doi = 10.1097/SLA.0000000000004644 | url = }} macrophages, blood monocytes, monocyte-derived dendritic cells,{{cite journal | vauthors = Keiran N, Ceperuelo-Mallafré V, Calvo E, Hernández-Alvarez MI, Ejarque M, Núñez-Roa C, Horrillo D, Maymó-Masip E, Rodríguez MM, Fradera R, de la Rosa JV, Jorba R, Megia A, Zorzano A, Medina-Gómez G, Serena C, Castrillo A, Vendrell J, Fernández-Veledo S | title = SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity | journal = Nature Immunology | volume = 20 | issue = 5 | pages = 581–592 | date = May 2019 | pmid = 30962591 | doi = 10.1038/s41590-019-0372-7 | hdl = 10261/189024 | s2cid = 102353378 | url = | hdl-access = free }}{{cite journal | vauthors = Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N, Schwärzler C, Junt T, Voshol H, Meingassner JG, Mao X, Werner G, Rot A, Carballido JM | title = Triggering the succinate receptor GPR91 on dendritic cells enhances immunity | journal = Nature Immunology | volume = 9 | issue = 11 | pages = 1261–9 | date = November 2008 | pmid = 18820681 | doi = 10.1038/ni.1657 | s2cid = 23526117 | url = }} CD34⁺ progenitor cells (i.e., bone marrow hematopoietic stem cells used therapeutically to restore hematopoiesis{{cite journal | vauthors = Prasad M, Corban MT, Henry TD, Dietz AB, Lerman LO, Lerman A | title = Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease | journal = Cardiovascular Research | volume = 116 | issue = 8 | pages = 1424–1433 | date = July 2020 | pmid = 32022845 | doi = 10.1093/cvr/cvaa027 | url = }}), blood platelets, megakaryocytes (i.e., platelet-producing cells), erythroblasts (i.e., red blood cell precursors), and the erythroleukemia cell line, TF-1;{{cite journal | vauthors = Hakak Y, Lehmann-Bruinsma K, Phillips S, Le T, Liaw C, Connolly DT, Behan DP | title = The role of the GPR91 ligand succinate in hematopoiesis | journal = Journal of Leukocyte Biology | volume = 85 | issue = 5 | pages = 837–43 | date = May 2009 | pmid = 19204147 | doi = 10.1189/jlb.1008618 | s2cid = 2248388 | url = }} c) adipocytes (i.e., fat cells);{{cite journal | vauthors = Villanueva-Carmona T, Cedó L, Madeira A, Ceperuelo-Mallafré V, Rodríguez-Peña MM, Núñez-Roa C, Maymó-Masip E, Repollés-de-Dalmau M, Badia J, Keiran N, Mirasierra M, Pimenta-Lopes C, Sabadell-Basallote J, Bosch R, Caubet L, Escolà-Gil JC, Fernández-Real JM, Vilarrasa N, Ventura F, Vallejo M, Vendrell J, Fernández-Veledo S | title = SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression | journal = Cell Metabolism | volume = 35 | issue = 4 | pages = 601–619.e10 | date = April 2023 | pmid = 36977414 | doi = 10.1016/j.cmet.2023.03.004 | s2cid = 257776817 | url = | doi-access = free | hdl = 10261/350284 | hdl-access = free }} d) endothelial cells in the veins and arteries of the placenta{{cite journal | vauthors = Atallah R, Gindlhuber J, Platzer W, Bärnthaler T, Tatzl E, Toller W, Strutz J, Rittchen S, Luschnig P, Birner-Gruenberger R, Wadsack C, Heinemann A | title = SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes | journal = International Journal of Molecular Sciences | volume = 22 | issue = 21 | date = November 2021 | page = 12048 | pmid = 34769478 | pmc = 8585094 | doi = 10.3390/ijms222112048 | doi-access = free | url = }} and umbilical cord;{{cite journal | vauthors = Mu X, Zhao T, Xu C, Shi W, Geng B, Shen J, Zhang C, Pan J, Yang J, Hu S, Lv Y, Wen H, You Q | title = Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation | journal = Oncotarget | volume = 8 | issue = 8 | pages = 13174–13185 | date = February 2017 | pmid = 28061458 | pmc = 5355086 | doi = 10.18632/oncotarget.14485 | url = }} e) human umbilical vein endothelial cells; f) epithelial cells, fibroblasts, and certain cells in the lamina propria of the small and large intestines;{{cite journal | vauthors = Macias-Ceja DC, Ortiz-Masiá D, Salvador P, Gisbert-Ferrándiz L, Hernández C, Hausmann M, Rogler G, Esplugues JV, Hinojosa J, Alós R, Navarro F, Cosin-Roger J, Calatayud S, Barrachina MD | title = Succinate receptor mediates intestinal inflammation and fibrosis | journal = Mucosal Immunology | volume = 12 | issue = 1 | pages = 178–187 | date = January 2019 | pmid = 30279517 | doi = 10.1038/s41385-018-0087-3 | url = | doi-access = free }} g) mast cells; h) HK-2 cells (a kidney proximal tubule epithelial non-cancerous cell line);{{cite journal | vauthors = Pu M, Zhang J, Zeng Y, Hong F, Qi W, Yang X, Gao G, Zhou T | title = Succinate-SUCNR1 induces renal tubular cell apoptosis | journal = American Journal of Physiology. Cell Physiology | volume = 324 | issue = 2 | pages = C467–C476 | date = February 2023 | pmid = 36622070 | doi = 10.1152/ajpcell.00327.2022 | s2cid = 255544096 | url = }} i) A549 lung, PC3 prostate, and HT-29 colin cancer cell lines;{{cite journal | vauthors = Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, Yeh CC, Peng YJ, Kuo YY, Wen HT, Lin HC, Hsiao CW, Wu KK, Kung HJ, Hsu YJ, Kuo CC | title = Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor | journal = Molecular Cell | volume = 77 | issue = 2 | pages = 213–227.e5 | date = January 2020 | pmid = 31735641 | doi = 10.1016/j.molcel.2019.10.023 | url = | doi-access = free }}{{cite journal | vauthors = Chen J, Cao L, Ma J, Yue C, Zhu D, An R, Wang X, Guo Y, Gu B | title = HDAC8 Promotes Liver Metastasis of Colorectal Cancer via Inhibition of IRF1 and Upregulation of SUCNR1 | journal = Oxidative Medicine and Cellular Longevity | volume = 2022 | issue = | pages = 2815187 | date = 2022 | pmid = 36035205 | pmc = 9400431 | doi = 10.1155/2022/2815187 | doi-access = free | url = }} j) a subset (10%) of nasal solitary chemosensory cells;{{cite journal | vauthors = Sell EA, Tan LH, Lin C, Bosso JV, Palmer JN, Adappa ND, Lee RJ, Kohanski MA, Reed DR, Cohen NA | title = Microbial metabolite succinate activates solitary chemosensory cells in the human sinonasal epithelium | journal = International Forum of Allergy & Rhinology | volume = 13 | issue = 8 | pages = 1525–1534 | date = August 2023 | pmid = 36565436 | doi = 10.1002/alr.23104 | s2cid = 255116741 | url = }} and k) cells in the retina, particularly retinal pigment epithelium cells.{{cite journal | vauthors = Louer EM, Lorés-Motta L, Ion AM, Den Hollander AI, Deen PM | title = Single nucleotide polymorphism rs13079080 is associated with differential regulation of the succinate receptor 1 (SUCNR1) gene by miRNA-4470 | journal = RNA Biology | volume = 16 | issue = 11 | pages = 1547–1554 | date = November 2019 | pmid = 31304868 | pmc = 6779389 | doi = 10.1080/15476286.2019.1643100 | url = }}

Succinate appears to be the primary agent that fully activates human SUCNR1. None of 800 tested compounds and 200 tested carboxylic acids fully activated SUCNR1 except for a) oxaloacetate, malate, α-ketoglutarate{{cite journal | vauthors = Trauelsen M, Rexen Ulven E, Hjorth SA, Brvar M, Monaco C, Frimurer TM, Schwartz TW | title = Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91 | journal = Molecular Metabolism | volume = 6 | issue = 12 | pages = 1585–1596 | date = December 2017 | pmid = 29157600 | pmc = 5699910 | doi = 10.1016/j.molmet.2017.09.005 | url = }} (α-ketoglutarate also activates the OXGR1 GPR receptor{{cite journal | vauthors = Cherif H, Duhamel F, Cécyre B, Bouchard A, Quintal A, Chemtob S, Bouchard JF | title = Receptors of intermediates of carbohydrate metabolism, GPR91 and GPR99, mediate axon growth | journal = PLOS Biology | volume = 16 | issue = 5 | pages = e2003619 | date = May 2018 | pmid = 29771909 | pmc = 5976209 | doi = 10.1371/journal.pbio.2003619 | doi-access = free | url = }}), and methylmalonate but were 5- to 10-fold less potent than succinate in doing so and b) two compounds/chemicals, cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid, which were respectively similar to and 10- to 20-fold more potent than succinate in activating SUCNR1.{{cite journal | vauthors = Geubelle P, Gilissen J, Dilly S, Poma L, Dupuis N, Laschet C, Abboud D, Inoue A, Jouret F, Pirotte B, Hanson J | title = Identification and pharmacological characterization of succinate receptor agonists | journal = British Journal of Pharmacology | volume = 174 | issue = 9 | pages = 796–808 | date = May 2017 | pmid = 28160606 | pmc = 5386996 | doi = 10.1111/bph.13738 | url = }} Agents that have been found to inhibit SUCNCR1 activation include NF-56-EJ40,{{cite journal | vauthors = Atallah R, Olschewski A, Heinemann A | title = Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1 | journal = Biomedicines | volume = 10 | issue = 12 | date = December 2022 | page = 3089 | pmid = 36551845 | pmc = 9775124 | doi = 10.3390/biomedicines10123089 | doi-access = free | url = }} 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, and three compounds identified as 2c, 4c, and 5g.{{cite journal | vauthors = Bhuniya D, Umrani D, Dave B, Salunke D, Kukreja G, Gundu J, Naykodi M, Shaikh NS, Shitole P, Kurhade S, De S, Majumdar S, Reddy SB, Tambe S, Shejul Y, Chugh A, Palle VP, Mookhtiar KA, Cully D, Vacca J, Chakravarty PK, Nargund RP, Wright SD, Graziano MP, Singh SB, Roy S, Cai TQ | title = Discovery of a potent and selective small molecule hGPR91 antagonist | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 12 | pages = 3596–602 | date = June 2011 | pmid = 21571530 | doi = 10.1016/j.bmcl.2011.04.091 | url = }} 4'-O-methylbavachadone, an active ingredient of the Chinese herbal remedy fructus psoraleae, has been reported to inhibit the binding of succinate to SUCNR1.{{cite journal | vauthors = Sun H, Zhu G, Ling S, Liu J, Xu JW | title = 4'‑O‑methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway | journal = Experimental and Therapeutic Medicine | volume = 25 | issue = 4 | pages = 172 | date = April 2023 | pmid = 37006873 | pmc = 10061262 | doi = 10.3892/etm.2023.11871 | url = }}{{cite journal | vauthors = An YA, Chen S, Deng Y, Wang ZV, Funcke JB, Shah M, Shan B, Gordillo R, Yoshino J, Klein S, Kusminski CM, Scherer PE | title = The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis | journal = Journal of Hepatology | volume = 75 | issue = 2 | pages = 387–399 | date = August 2021 | pmid = 33746082 | pmc = 8292187 | doi = 10.1016/j.jhep.2021.03.006 | url = }}

Succinate inhibited the isolated fat tissues of mice from the isoproterenol-induce metabolic hydrolysis of their triglycerides into free fatty acids and glycerol, i.e., it inhibited stimulus-induced lipolysis. However, succinate did not effectively inhibit isoproterenol-stimulated lipolysis in mouse fat tissues that lacked SUCNR1 due to the knockout of their Sucnr1 genes. This anti-lipolysis action was therefore due at least in part to succinate's activation of SUCNR1. In related studies, Sucnr1 gene knockout mice fed a high-fat diet for 20 weeks had significantly higher body fat content than wild type mice (i.e., mice expressing normal levels of SUCNR1) fed this diet.{{cite journal | vauthors = McCreath KJ, Espada S, Gálvez BG, Benito M, de Molina A, Sepúlveda P, Cervera AM | title = Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity | journal = Diabetes | volume = 64 | issue = 4 | pages = 1154–67 | date = April 2015 | pmid = 25352636 | doi = 10.2337/db14-0346 | url = }} These differences did not occur or were minimal in mice fed a standard diet. Furthermore, the total body weights of Sucnr1 gene knockout mice on the high-fat diet for 4–12 weeks was higher than wild type mice on this diet but by 16 weeks was similar to wild type mice on the standard diet. Thus, SUCNR1 inhibited one feature of high-fat diet-induced obesity, the accumulation of excessive body fat, but had only short-term effects on another of its features, the development of excessive total body weight. Further studies in animal models and human fat tissues are needed in order to understand more fully SUCNR1's role in and relevancy to human lipolysis and obesity.

In addition to evidencing increased levels of lipolysis (see preceding section), Sucnr1 gene knockout mice had increased plasma glucose levels, impaired glucose tolerance (i.e., abnormally slow decreases in blood glucose levels in response to a glucose challenge), and increased rates of resting metabolic activity. Some of these symptoms are features of human prediabetes. A study of 1152 type 2 diabetic versus 1152 heathy individuals conducted in China reported that three single-nucleotide polymorphisms (i.e., SNPs) in their SUCNR1 genes (viz., rs73168929, rs1557213 and rs17151584) were significantly more common in the diabetic individuals.{{cite journal | vauthors = Du B, Jia X, Tian W, Yan X, Wang N, Cai D, Li X, Zhang H, Jin M, Wu N, Qiu C, Zhang Q | title = Associations of SUCNR1, GRK4, CAMK1D gene polymorphisms and the susceptibility of type 2 diabetes mellitus and essential hypertension in a northern Chinese Han population | journal = Journal of Diabetes and Its Complications | volume = 35 | issue = 1 | pages = 107752 | date = January 2021 | pmid = 33127268 | doi = 10.1016/j.jdiacomp.2020.107752 | s2cid = 225126632 | url = }} (A SNP is a variation in a specifically identified nucleotide of a gene; the variation may alter the production, structure, and/or function of the protein directed to be made by the gene and is often identified as being associated with, and a potential cause of, a specific disease(s).{{cite book | vauthors = Zhang J, Yang J, Wen C | title = Plant Genotyping | chapter = A New SNP Genotyping Technology by Target SNP-Seq | series = Methods in Molecular Biology | volume = 2638 | pages = 365–371 | date = 2023 | pmid = 36781656 | doi = 10.1007/978-1-0716-3024-2_26 | isbn = 978-1-0716-3023-5 | chapter-url = }}). Gestational diabetes is a persistent increase in blood sugar levels first recognized during a woman's pregnancy and reversing after this pregnancy but over the following 3–6 years associated with a high risk of developing type 2 diabetes.{{cite journal | vauthors = Li Q, Zhu Y, Wang J, Zhang Y, Pan Y, Gu R, Guo X, Wei L | title = Sedentary behaviors and gestational diabetes mellitus: A systematic review | journal = The Journal of Obstetrics and Gynaecology Research | volume = 48 | issue = 2 | pages = 285–299 | date = February 2022 | pmid = 34750937 | doi = 10.1111/jog.15090 | s2cid = 243863298 | url = }} A study of gestational diabetes patients reported that their placental tissues had significantly higher levels of succinate and SUCNR1 than the placentas of non-diabetic women. The study also reported that human umbilical vein endothelial cells (HUVECs) cultured in media with high levels of glucose (i.e., 20 mmol/l) expressed significantly higher levels of SUCNR1 than cells cultured in lower glucose levels (5.5 mmol/l); that succinate stimulated cultured HUVECs to proliferate, migrate, and heal wounds in assays of these functions; and that HUVECs that had their Sucnr1 gene knocked down showed significantly reduce proliferation and migration responses to succinate. Overall, these findings suggest that: a) SUCNR1 modulates glucose metabolism, glucose levels, and insulin resistance to cause a prediabetes-like condition in mice; b) certain SNP variants in the SUCNR1 gene are associated with and may contribute to the development of type 2 diabetes in humans; c) high levels of glucose stimulate HUVECs to increase their levels of SUCNR1; d) succinate-induced activation of the SUCNR1 on HUVECs stimulates their proliferation and motility; e) increases in placental succinate and SUCRN1 levels are closely associated with gestational diabetes; and f) SUCNR1 in the human placenta may be a target for treating excessive placental endothelial cell proliferation.

Metabolic dysfunction–associated steatotic liver disease (i.e., MASLD), previously termed nonalcoholic fatty liver disease (i.e., NAFLD),{{cite journal | vauthors = Chan WK, Chuah KH, Rajaram RB, Lim LL, Ratnasingam J, Vethakkan SR | title = Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review | journal = Journal of Obesity & Metabolic Syndrome | volume = 32 | issue = 3 | pages = 197–213 | date = September 2023 | pmid = 37700494 | pmc = 10583766 | doi = 10.7570/jomes23052 | url = }} is the excessive accumulation of fat in the liver resulting from metabolic disorders such as diabetes, the metabolic syndrome, obesity, and hyperlipidemia but not from excessive alcohol consumption. Nonalcoholic steatohepatitis (i.e., NASH), now termed steatotic liver disease (i.e., SLD), is a stage of MASLD that has higher levels of liver inflammation and may progress to advanced fibrosis, cirrhosis, liver failure,{{cite journal | vauthors = Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, Kassir R, Singhal R, Mahawar K, Ramnarain D | title = Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss | journal = BMC Endocrine Disorders | volume = 22 | issue = 1 | pages = 63 | date = March 2022 | pmid = 35287643 | pmc = 8919523 | doi = 10.1186/s12902-022-00980-1 | doi-access = free | url = }} and liver cancer.{{cite journal | vauthors = Eskridge W, Cryer DR, Schattenberg JM, Gastaldelli A, Malhi H, Allen AM, Noureddin M, Sanyal AJ | title = Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis: The Patient and Physician Perspective | journal = Journal of Clinical Medicine | volume = 12 | issue = 19 | date = September 2023 | page = 6216 | pmid = 37834859 | pmc = 10573476 | doi = 10.3390/jcm12196216 | doi-access = free | url = }} Studies in mouse models of MASLD progressing to hepatic fibrosis have reported that: a) the levels of succinate (as well as 3-hydroxybutyrate and malate) were higher in the livers of mice on a high-fat diet than mice on a normal diet; b) the levels of SUCNR1 in the liver's hepatic stellate cells were far greater in mice on the high-fat diet than in mice on a normal diet;{{cite journal | vauthors = Liu XJ, Xie L, Du K, Liu C, Zhang NP, Gu CJ, Wang Y, Abdelmalek MF, Dong WY, Liu XP, Niu C, Yang C, Diehl AM, Wu J | title = Succinate-GPR-91 receptor signaling is responsible for nonalcoholic steatohepatitis-associated fibrosis: Effects of DHA supplementation | journal = Liver International| volume = 40 | issue = 4 | pages = 830–843 | date = April 2020 | pmid = 31903720 | pmc = 9990138 | doi = 10.1111/liv.14370 | url = }} c) contrasting results were reported in studies finding that Sucnr1 gene knockdown mice fed a MASLD-inducing methionine- and choline-deficient diet had lower levels of steatosis (i.e., fat accumulation) and fibrosis in their livers than wild type mice{{cite journal | vauthors = Li YH, Choi DH, Lee EH, Seo SR, Lee S, Cho EH | title = Sirtuin 3 (SIRT3) Regulates α-Smooth Muscle Actin (α-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells | journal = The Journal of Biological Chemistry | volume = 291 | issue = 19 | pages = 10277–92 | date = May 2016 | pmid = 26912655 | pmc = 4858976 | doi = 10.1074/jbc.M115.692244 | doi-access = free | url = }} but other studies finding that Sucnr1 gene knockdown mice feeding on a high-fat, choline deficient MASLD-inducing diet developed higher levels of steatosis and inflammation along with lower levels of fibrosis and glycogen in their livers than wild type mice{{cite journal | vauthors = Marsal-Beltran A, Rodríguez-Castellano A, Astiarraga B, Calvo E, Rada P, Madeira A, Rodríguez-Peña MM, Llauradó G, Núñez-Roa C, Gómez-Santos B, Maymó-Masip E, Bosch R, Frutos MD, Moreno-Navarrete JM, Ramos-Molina B, Aspichueta P, Joven J, Fernández-Real JM, Quer JC, Valverde ÁM, Pardo A, Vendrell J, Ceperuelo-Mallafré V, Fernández-Veledo S | title = Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD | journal = Metabolism: Clinical and Experimental | volume = 145 | issue = | pages = 155630 | date = August 2023 | pmid = 37315889 | doi = 10.1016/j.metabol.2023.155630 | url = | doi-access = free | hdl = 10230/59377 | hdl-access = free }} (These different results may reflect differences in the diet compositions, durations, and/or stages of diseases examined.); d) succinate stimulated increases in the expression of SUCNR1 in cultured hepatic satellite cells that were isolated from the livers of rats or humans; e) analyses of the MASLD livers from patients showed that their livers' fibrosis levels increased with their livers' SUCNR1 levels. and f) the circulating blood levels of succinate were higher in 86 patients with higher fatty liver indexes than in 5 healthy individuals (this index is a composite score based on an individual's waist circumferences, basal metabolic rate, blood triglyceride level, and blood gamma-glutamyl transferase level). Further detailed studies are needed to clarify the role(s) of SUCNR1 in the progression of MASLD to more severe liver disease in mice and humans. The studies do suggest that the fatty liver index may be a useful non-invasive indicator of MASLD in humans.

Mice treated with intravenous succinate for 5 consecutive days developed ventricular hypertrophy as defined by increases in the size of their cardiac muscle cells. These increases did not occur in SUCNR1 gene knockout mice. Furthermore, 8 patients diagnosed with acute myocardial infarction and/or chronic coronary artery disease had readily detectable serum blood levels of succinate whereas 6 healthy individuals had undetectable serum levels of succinate.{{cite journal | vauthors = Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, Ladeira LO, Resende RR, Botoni FA, Barrouin Melo M, Lima CX, Carballido JM, Cunha TM, Menezes GB, Guatimosim S, Leite MF | title = Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation | journal = Cell Communication and Signaling | volume = 12 | issue = | pages = 78 | date = December 2014 | pmid = 25539979 | pmc = 4296677 | doi = 10.1186/s12964-014-0078-2 | doi-access = free | url = }} These studies suggest that the succinate-induced activation of SUCNR1 plays a key role in pathological cardiomyocyte hypertrophy in mice and support studies to determine if it does so in humans.

Elderly individuals, even if otherwise healthy, can develop cardiac fibrosis severe enough to promote the development of a form of heart failure termed heart failure with preserved ejection fraction, i.e., HFpEF. HFpEF is characterized by diastolic dysfunction (i.e., poor relaxation of the heart's left ventricle) with normal systolic contraction.{{cite journal | vauthors = Maryniak A, Maisuradze N, Ahmed R, Biskupski P, Jayaraj J, Budzikowski AS | title = Heart failure with preserved ejection fraction update: A review of clinical trials and new therapeutic considerations | journal = Cardiology Journal | volume = 29 | issue = 4 | pages = 670–679 | date = 2022 | pmid = 35762077 | pmc = 9273251 | doi = 10.5603/CJ.a2022.0051 | url = }}

SUCNR1 is expressed by various cell types in the kidneys of mice including cells in the epithelium of renal tubules, endothelial cells in the glomerulus, and macula densa (i.e., tightly packed cell areas in the ascending limb of the loop of Henle).{{cite journal | vauthors = Vargas SL, Toma I, Kang JJ, Meer EJ, Peti-Peterdi J | title = Activation of the succinate receptor GPR91 in macula densa cells causes renin release | journal = Journal of the American Society of Nephrology | volume = 20 | issue = 5 | pages = 1002–11 | date = May 2009 | pmid = 19389848 | pmc = 2678039 | doi = 10.1681/ASN.2008070740 | url = }} Studies have shown that, compared to male mice who drank normal water, male mice who drank water containing 4% sodium succinate for 12 weeks developed greatly increased serum, urine, and kidney succinate levels; reduced amounts of urine output without changes in water intake; and pathological changes in their kidneys, e.g., detachment of their proximal tubule brush border epithelial cells, dilation of and urinary cast formation in their renal tubules, vacuolar degeneration (i.e., formation of non-livid vacuoles in the cytoplasm) of their renal tubular cells, and increases in the number of kidney cells dying due to apoptosis. Succinate also caused apoptosis in cultured human kidney-2 cells but its apoptosis-inducing action was greatly reduced in human kidney-2 cells that had their Sucnr1 gene knocked down. These findings, while requiring further studies including some on female mice, suggest that succinate injures kidney tissues in female mice and cultured human kidney-2 cells. This injury involves SUCNR1 activation in cultured human kidney cells.

Age-related macular degeneration (AMD) is a disease of the macula (i.e., pigmented area in the center of the retina) that causes progressively increasing loses in central vision with peripheral vision remaining relatively intact (see central versus peripheral vision). By definition, the diagnosis of AMD is restricted to persons older than 55 years. AMD is divided into two forms, dry AMD characterized by the development of numerous large drusen (i.e., lipid-rich deposits that lie beneath the retinal pigment epithelium) and wet AMD characterized by the excessive growth of blood vessels (i.e. neovascularization) beneath the macula and the leakage from these vessels of blood and fluid into the central retina.{{cite journal | vauthors = Guymer RH, Campbell TG | title = Age-related macular degeneration | journal = Lancet | volume = 401 | issue = 10386 | pages = 1459–1472 | date = April 2023 | pmid = 36996856 | doi = 10.1016/S0140-6736(22)02609-5 | s2cid = 257856748 | url = }} Typically, AMD begins as dry AMD but at varying times thereafter may be followed by neovascularizations in and around the maucla, i.e., by its progression to wet AMD.{{cite journal | vauthors = Shen T, Lin R, Hu C, Yu D, Ren C, Li T, Zhu M, Wan Z, Su T, Wu Y, Cai W, Yu J | title = Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization | journal = Journal of Neuroinflammation | volume = 20 | issue = 1 | pages = 308 | date = December 2023 | pmid = 38129891 | doi = 10.1186/s12974-023-02998-1 | doi-access = free | pmc = 10734053 | url = }} Studies in mice showed that the expression of SUCNR1 in the retinal pigment epithelium decreased progressively with age and that Sucnr1 gene knockout mice had signs of premature sub-retinal damage similar to that in dry AMD, e.g., the accumulation of oxidized low-density lipoproteins, abnormal thickening of Bruch's membrane, and increased subretinal microglia. These findings suggest that deficiencies in SUCNR1 are a possible contributing factor to the pathogenesis of dry AMD in mice.{{cite journal | vauthors = Favret S, Binet F, Lapalme E, Leboeuf D, Carbadillo J, Rubic T, Picard E, Mawambo G, Tetreault N, Joyal JS, Chemtob S, Sennlaub F, Sangiovanni JP, Guimond M, Sapieha P | title = Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions | journal = Aging | volume = 5 | issue = 6 | pages = 427–44 | date = June 2013 | pmid = 23833031 | pmc = 3832265 | doi = 10.18632/aging.100563 | url = }} A study of 5 patients with wet AMD showed that they had significantly higher levels of succinate in their eyes' aqueous humor than 5 patients who did not have AMD. The high levels of succinate in wet AMD may have acted to promote the development of the neovasculariztions (see Neovascularization section) which underlie the progression of dry to wet AMD. Finally, a gene analysis of 925 individuals with advanced dry AMD and 1199 AMD-free individuals revealed that there was an increased risk of developing advanced dry AMD in individuals that had single-nucleotide polymorphism variants (i.e., rs13315275) in their SUCNR1 gene. Overall, these studies suggest that SUCNR1 acts to prevent or slow the development of dry AMD in mice and humans but may promote the progression of dry to wet AMD in humans. Further studies comparing the aqueous humor succinate levels in individuals with wet AMD to non-AMD and adding studies comparing aqueous humor succinate levels of wet to dry AMD are needed to further test the hypothesis that succinate promotes the progression of dry to wet AMD.

Retinopathy of prematurity (ROP) is a major cause of visual impairment and blindness in prematurely born infants who received oxygen therapy to combat their presumed low levels of retinal oxygen.{{cite journal | vauthors = Yulia DE, Soeharto DA | title = One year follow-up of intravitreal bevacizumab injection in Aggressive Retinopathy of Prematurity at Indonesian national referral hospital: Case series | journal = Annals of Medicine and Surgery | volume = 84 | pages = 104853 | date = December 2022 | pmid = 36536703 | pmc = 9758374 | doi = 10.1016/j.amsu.2022.104853 }} Animal studies suggest that low levels of retinal oxygen increase the eye's production of succinate; the high levels of succinate activate retinal SUCNR1 which in turn stimulates neovascularization. In ROP, this retinal neovascularization is excessive, enters the aqueous humor by penetrating through the vitreous membrane that separates the aqueous humor from the retina, and causes traction on the retina, bleeding, and visual impairments including blindness.{{cite journal | vauthors = Hu J, Li T, Du X, Wu Q, Le YZ | title = G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases | journal = Vision Research | volume = 139 | issue = | pages = 59–64 | date = October 2017 | pmid = 28539261 | pmc = 5723215 | doi = 10.1016/j.visres.2017.05.001 | url = }} SUCNR1 is expressed by retinal pigment epithelium cells in humans and ganglion cells in rats.{{cite journal | vauthors = Joyal JS, Omri S, Sitaras N, Rivera JC, Sapieha P, Chemtob S | title = Neovascularization in retinopathy of prematurity: opposing actions of neuronal factors GPR91 and semaphorins 3A | journal = Acta Paediatrica | volume = 101 | issue = 8 | pages = 819–26 | date = August 2012 | pmid = 22497252 | doi = 10.1111/j.1651-2227.2012.02692.x | s2cid = 38844477 | url = }} In a model of hypoxia-induced retinopathy of prematurity, rat pups who received oxygen therapy developed under-vascularized retinas. Succinate treatment of these rats promoted neovascularization in their under-vascularized retinas but was significantly less effective in doing so in Susnr1 gene knockdown rats.{{cite journal | vauthors = Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, Honoré JC, Kermorvant-Duchemin E, Varma DR, Tremblay S, Leduc M, Rihakova L, Hardy P, Klein WH, Mu X, Mamer O, Lachapelle P, Di Polo A, Beauséjour C, Andelfinger G, Mitchell G, Sennlaub F, Chemtob S | title = The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis | journal = Nature Medicine | volume = 14 | issue = 10 | pages = 1067–76 | date = October 2008 | pmid = 18836459 | doi = 10.1038/nm.1873 | s2cid = 6249205 | url = }} Thus, succinate-induced activation of SUCNR1 appears to be a signaling pathway that in ROP stimulates the excessive formation new blood vessels and thereby leads to visual defects. Inhibiting the activation of SUCNR1 may prove to be useful for treating infants with excessive retinal neovascularization due to ROP.

Diabetic retinopathy is due at least in part to low levels of oxygen in the retina.{{cite journal | vauthors = Catrina SB, Zheng X | title = Hypoxia and hypoxia-inducible factors in diabetes and its complications | journal = Diabetologia | volume = 64 | issue = 4 | pages = 709–716 | date = April 2021 | pmid = 33496820 | pmc = 7940280 | doi = 10.1007/s00125-021-05380-z | url = }} In a model of streptozotocin-induced diabetic retinopathy, rats developed high blood glucose levels, increased levels of succinate in their retinas, retinal neovascularization, increased permeability of their retinal blood vessels, and thickening of their capillary basement membranes. These effects were significantly reduced in streptozotocin-treated mice who had the levels of SUCNRI in their eyes knocked down by the intraocular injection of lenticular virus containing shRNA directed against their Sucnr1 gene (see Delivery of shRNA).{{cite journal | vauthors = Li T, Hu J, Du S, Chen Y, Wang S, Wu Q | title = ERK1/2/COX-2/PGE2 signaling pathway mediates GPR91-dependent VEGF release in streptozotocin-induced diabetes | journal = Molecular Vision | volume = 20 | issue = | pages = 1109–21 | date = 2014 | pmid = 25324681 | pmc = 4119234 | doi = | url = }} A study of rat pups that used oxygen-deprivation as a model of diabetic retinopathy likewise found that the intraocular injection of shRNA directed against the Sucnrn1 gene suppressed their development of diabetic retinopathy. Studies in humans on the role of the succinate-SUCNR1 axis in diabetic retinopathy could lead to the identification of new therapeutic strategies, i.e., the inhibition of SUCNR1 activation, to treat this disorder.{{cite journal | vauthors = Li T, Hu J, Gao F, Du X, Chen Y, Wu Q | title = Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy | journal = Scientific Reports | volume = 7 | issue = | pages = 45807 | date = April 2017 | pmid = 28374767 | pmc = 5379554 | doi = 10.1038/srep45807 | bibcode = 2017NatSR...745807L | url = }}

In a model of muscle ischemia due to reduced blood flow, mice had their right hindlimb femoral artery ligated and partially resected. Following this procedure, their right quadriceps leg muscle was injected daily for 15 days with succinate or the buffered solution that carried the succinate. Compared to buffer-treated mice, succinate-treated mice had significantly higher levels of SUCNR1 in the muscles of their afflicted leg, better blood flow to the afflicted leg, and better recovery of function in their afflicted leg. Thus, succinate injections promoted the neovascularization and thereby recovery of function in the ischemia-damaged limbs of mice.{{cite journal | vauthors = Moyon A, Garrigue P, Balasse L, Fernandez S, Brige P, Bouhlel A, Hache G, Dignat-George F, Taïeb D, Guillet B | title = Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study | journal = Cells | volume = 10 | issue = 4 | date = April 2021 | page = 795 | pmid = 33918298 | pmc = 8066129 | doi = 10.3390/cells10040795 | doi-access = free | url = }} In a cerebral cortex hypoxia-ischemia Rice-Vannucci model{{cite journal | vauthors = Rice JE, Vannucci RC, Brierley JB | title = The influence of immaturity on hypoxic-ischemic brain damage in the rat | journal = Annals of Neurology | volume = 9 | issue = 2 | pages = 131–41 | date = February 1981 | pmid = 7235629 | doi = 10.1002/ana.410090206 | s2cid = 34124161 | url = }} of permanent unilateral common carotid artery occlusion, 7 day old mouse pups were exposed to 8% oxygen (normal air level of oxygen is ~21%) for 90 minutes. Wild type and Sucnr1 gene-knockout mice showed a 3-fold increase in the succinate levels of the penumbra (i.e., area surrounding) the ischemic brain tissue 90 minutes after exposure to the 8% oxygen; these succinate levels returned to baseline values within the next 60 minutes. One day after exposure to 8% oxygen, wild type mice showed decreased followed in two days by increased microvascular densities in the penumbral regions whereas Sucnr1 gene knockout mice showed the decrease one day after but not the subsequent increase in penumbral vascularization. Finally, injections of succinate into the mice's cerebral ventricle reduced the size of the infarct (i.e., dead tissue) by more than 50% as determined 3 days after their exposure to low oxygen levels; the infarct size was not reduced in Sucnr1 gene knockout mice. These finding indicate that the succinate-SUCNR1 axis promotes neovascularization and thereby reduces the infarct size after vascular cerebral artery occlusion in mouse pups{{cite journal | vauthors = Hamel D, Sanchez M, Duhamel F, Roy O, Honoré JC, Noueihed B, Zhou T, Nadeau-Vallée M, Hou X, Lavoie JC, Mitchell G, Mamer OA, Chemtob S | title = G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 34 | issue = 2 | pages = 285–93 | date = February 2014 | pmid = 24285580 | doi = 10.1161/ATVBAHA.113.302131 | url = }} and suggest the therapeutic possibility that stimulating SUCNR1 may reduce the severity of vascular occlusion diseases such as strokes in humans.

Epithelial–mesenchymal transition (EMT) is the transformation of stationary epithelial cells into mobile mesenchymal cells. Cells undergo EMT mainly when they need to be mobile such as during their embryonic development or stressful conditions such as wound healing and the need to repair a damaged tissue.{{cite journal | vauthors = Turano M, Vicidomini R, Cammarota F, D'Agostino V, Duraturo F, Izzo P, Rosa M | title = The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation | journal = Biomedicines | volume = 11 | issue = 5 | date = May 2023 | page = 1428 | pmid = 37239099 | pmc = 10216699 | doi = 10.3390/biomedicines11051428 | doi-access = free | url = }} However, recent studies indicate that the cells in localized epithelial cancers can similarly transform into mesenchymal-like cells and thereby attain the ability to migrate, invade adjacent tissues, and metastasize.{{cite journal | vauthors = Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA | title = Mechanisms of cancer metastasis | journal = Seminars in Cancer Biology | volume = 87 | issue = | pages = 17–31 | date = December 2022 | pmid = 36354098 | doi = 10.1016/j.semcancer.2022.10.006 | url = | doi-access = free }} This pro-malignant transformation may be due at least in some cases to the activation of SUCNR1 by succinate. A) Cultured Lewis lung carcinoma epithelioid mouse cells and four human epithelioid cancer cell lines, A549 lung, PC3 prostate, MCF-7 breast, and HT-29 colon cells, secreted high amounts of succinate into their culture media whereas cultures of non-malignant macrophages isolated from the peritoneal cavity of mice did not secrete detectable amounts of succinate and cultured human gastric epithelial non-malignant cells secreted relatively small amounts of succinate into their culture media. B) Succinate stimulated the migration and tissue-invasiveness of cultured Lewis lung carcinoma, A549, PD3, MCF-7, and HT-29 cells in assays of cell motility and invasiveness. C) A549 cells treated with a short hairpin RNA that knocked down their levels of SUCNR1 had significantly reduced migration responses to succinate. D) A549 cells treated with succinate showed increases in SNAI1, a transcription factor that promotes EMT. E) Metformin (which is an inhibitor of EMT{{cite journal | vauthors = Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H | title = The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy | journal = Medicina (Kaunas, Lithuania) | volume = 58 | issue = 4 | date = March 2022 | page = 467 | pmid = 35454306 | pmc = 9032206 | doi = 10.3390/medicina58040467 | doi-access = free | url = }}) abolished the migration responses of A549 cells to succinate. F) Succinate stimulated the migration of Lewis lung carcinoma, A549, PC3, and HT-29 cells but did not do so when these cells were pretreated with an antibody that binds to and thereby blocks succinate from binding to SUCNR1. G) Mice injected subcutaneously with Lewis lung carcinoma cells had significantly higher levels of serum succinate 16 days after this injection compared to their pre-injection serum succinate levels. H) Serum succinate levels were significantly elevated in patients with lung cancer, squamous cell carcinomas of the head and neck,{{cite journal | vauthors = Terra X, Ceperuelo-Mallafré V, Merma C, Benaiges E, Bosch R, Castillo P, Flores JC, León X, Valduvieco I, Basté N, Cámara M, Lejeune M, Gumà J, Vendrell J, Vilaseca I, Fernández-Veledo S, Avilés-Jurado FX | title = Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker | journal = Cancers | volume = 13 | issue = 7 | date = April 2021 | page = 1653 | pmid = 33916314 | pmc = 8037494 | doi = 10.3390/cancers13071653 | doi-access = free | url = }} and the Cowden syndrome (a syndrome associated with extremely high rates of developing benign and malignant tumors). And, I) serum succinate levels are also elevated in patients with hereditary paragangliomas in the relatively uncommon cases of this disease that are caused by inactivating mutations in one of the four genes that encode for the four proteins that make up the succinate dehydrogenase heterotetrmer, i.e., the SDHD, SDHA, SDHC, and SDHB genes (inactivation of any one of these genes causes paraganglioma cells to produce excessive amounts of succinate).{{cite journal | vauthors = Lamy C, Tissot H, Faron M, Baudin E, Lamartina L, Pradon C, Al Ghuzlan A, Leboulleux S, Perfettini JL, Paci A, Hadoux J, Broutin S | title = Succinate: A Serum Biomarker of SDHB-Mutated Paragangliomas and Pheochromocytomas | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 107 | issue = 10 | pages = 2801–2810 | date = September 2022 | pmid = 35948272 | doi = 10.1210/clinem/dgac474 | s2cid = 251494576 | url = | doi-access = free }} (Serum succinate levels are not elevated in all cancers, e.g., breast cancer patients do not show significant elevations of serum succinate;{{cite journal | vauthors = Shekher A, Puneet, Awasthee N, Kumar U, Raj R, Kumar D, Gupta SC | title = Association of altered metabolic profiles and long non-coding RNAs expression with disease severity in breast cancer patients: analysis by 1H NMR spectroscopy and RT-q-PCR | journal = Metabolomics| volume = 19 | issue = 2 | pages = 8 | date = January 2023 | pmid = 36710275 | doi = 10.1007/s11306-023-01972-5 | s2cid = 256362645 | url = }} note also that MFC-7 cells do not express SUCNR1.{{cite journal | vauthors = Dallons M, Alpan E, Schepkens C, Tagliatti V, Colet JM | title = GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells | journal = Cells | volume = 9 | issue = 10 | date = September 2020 | page = 2177 | pmid = 32992522 | pmc = 7599858 | doi = 10.3390/cells9102177 | doi-access = free | url = }}) These studies suggest: that succinate stimulates SUCNR1 in A549 cells to transition from an epithelial to a mesenchymal phenotype and thereby increase their ability to migrate, invade tissues, and possibly metastasize; that A549, PC3, and HT-29 cells appear to also show SUCNR1-dependent EMT transformations by a SUCNR1-dependent mechanism; that paragangliomas caused by hereditary inactivating mutations in one of the four succinate dehydrogenase genes and possibly other types of cancers that overexpress succinate may be due at least in part to the activation of SUCNR1; and that high serum levels of succinate may indicate the presence of human cancers and thereby be useful markers to define the effectiveness of treating them.

Studies have implicated the succinate-SUCNR1 axis in the development of inflammatory bowel diseases, i.e., Crohn's disease, ulcerative colitis, infectious cholitis, and various other causes of inflammation in the small and/or large intestines. Studies in mice reported that the only cells expressing SUCNR1 in the small intestine and colon epithelium are tuft cells and that the colon has far fewer tuft cells than the small intestine. Mice drinking water containing 100 mM succinate for 7 days developed intestinal features of type 2 inflammation similar to those evoked by intestinal parasitic worm infections, i.e., their small intestines showed increased numbers of tuft cells and increased numbers and sizes of goblet cells. Mice drinking plain water and Sucnr1 gene knockout mice drinking the succinate-containing water did not show these changes.{{cite journal | vauthors = Lei W, Ren W, Ohmoto M, Urban JF, Matsumoto I, Margolskee RF, Jiang P | title = Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 21 | pages = 5552–5557 | date = May 2018 | pmid = 29735652 | pmc = 6003470 | doi = 10.1073/pnas.1720758115 | doi-access = free | bibcode = 2018PNAS..115.5552L | url = }} A second study also found that succinate-containing drinking water caused an intestinal type 2 inflammation response. The study also showed that gastrointestinal infection with a Trichomoniasis parasite was sufficient to induce a type 2 inflammatory response in wild type but not in Sucnr1 gene knockout mice. However, the same experiment examining the response to the gastrointestinal roundworm, Nippostrongylus brasiliensis, found that it caused similar type 2 inflammatory responses in Sucnr1 gene knockout mice and wild type mice.{{cite journal | vauthors = Nadjsombati MS, McGinty JW, Lyons-Cohen MR, Jaffe JB, DiPeso L, Schneider C, Miller CN, Pollack JL, Nagana Gowda GA, Fontana MF, Erle DJ, Anderson MS, Locksley RM, Raftery D, von Moltke J | title = Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit | journal = Immunity | volume = 49 | issue = 1 | pages = 33–41.e7 | date = July 2018 | pmid = 30021144 | pmc = 6084797 | doi = 10.1016/j.immuni.2018.06.016 | url = }} In a model of 2,4,6-trinitrobenzenesulfonic acid (i.e., TNBS)-induced inflammatory bowel disease, the administration of TNBS into the rectums of mice caused within 2 days losses in body weight, shortening of colon lengths, colon histological damage (e.g., inflammatory infiltrates and disruptions of the colon's epithelial architecture), and increased colon tissue levels of SUCNR1. Most of these findings were significantly reduced in SUCNR1 gene knockout mice. These studies indicate that high levels of intestinal succinate activate SUCNR1 to produce inflammatory bowel disease-like changes in the small intestines of mice, that intestinal infections with some but not all pathogens produce SUCNR1-dependent inflammatory bowel disease, and that the TNBS model of chemical-induced colitis is also caused by succinate's activation of SUCNR1. Other studies have reported that: a) patients with Crohn's disease have higher blood plasma levels of succinate than healthy individuals; b) Crohn's disease patients with active disease have higher blood serum levels of SUCNR1 than Crohn's disease patients with inactive disease; c) Crohn's disease patients have higher levels of succinate within the small intestine and higher SUCNR1 levels in their small intestine's walls than individuals without Crohn's disease;{{cite journal | vauthors = Monfort-Ferré D, Caro A, Menacho M, Martí M, Espina B, Boronat-Toscano A, Nuñez-Roa C, Seco J, Bautista M, Espín E, Megía A, Vendrell J, Fernández-Veledo S, Serena C | title = The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn's Disease | journal = Journal of Crohn's & Colitis | volume = 16 | issue = 10 | pages = 1571–1583 | date = November 2022 | pmid = 35554517 | pmc = 9624294 | doi = 10.1093/ecco-jcc/jjac069 | url = }} d) Crohn's disease patients have higher levels of succinate in the fibroblasts (fibroblasts make extracellular fibrous tissue) isolated from their small intestines than the fibroblasts isolated from the small intestines of patients without inflammatory bowel disease; e) the primary fibroblasts isolated from the intestinal tissue of Crohn's disease patients had higher levels of SUCNR1 than the fibroblasts isolated from the intestines of patients without inflammatory bowel disease; f) succinate stimulated increases in the levels of SUCNR1, two markers of fibrosis (COL1a1, α-SMA), the pro-fibrotic factor TGFβ and the pro-inflammatory cytokine IL1β in primary fibroblasts isolated from patients without inflammatory disease but was far less effective in doing so when these cells had their SUCNR1 levels knocked down; and g) SUCNR1 was significantly increased in the colon tissues of patients with ulcerative colitis compared to patients without inflammatory bowel disease.{{cite journal | vauthors = Bauset C, Lis-Lopez L, Coll S, Gisbert-Ferrándiz L, Macias-Ceja DC, Seco-Cervera M, Navarro F, Esplugues JV, Calatayud S, Ortiz-Masia D, Barrachina MD, Cosín-Roger J | title = SUCNR1 Mediates the Priming Step of the Inflammasome in Intestinal Epithelial Cells: Relevance in Ulcerative Colitis | journal = Biomedicines | volume = 10 | issue = 3 | date = February 2022 | page = 532 | pmid = 35327334 | pmc = 8945150 | doi = 10.3390/biomedicines10030532 | doi-access = free | url = }} These findings suggest that succinate-induced activation of SUCNR1 may promote the development of Crohn's disease and support studies to determine if succinate and SUCNR1 are similarly involved in the development of ulcerative colitis.

In a murine model of autoimmune arthritis, mice were sensitized to bovine serum albumin (i.e., BSA) by injecting methylated BSA (mBSA) into two sites in the dermis of their backs 14 and 21 days after their right knee was injected with mBSA and their left knee was injected with the solution used to carry mBSA. The mBSA-injected left knees of mice became two-fold larger in size (indicating an increase in inflammation) and had three-fold higher levels of succinate in their synovial (i.e., joint) fluids) than their left knees. Further analyses suggested that the SUCNR1-expressing macrophages in these joints were activated by the rising levels of succinate to elicit inflammation and thereby joint swelling.{{cite journal | vauthors = Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J, Zhang J, Muller A, Tigani B, Kneuer R, Patel S, Valeaux S, Gommermann N, Rubic-Schneider T, Junt T, Carballido JM | title = GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis | journal = The Journal of Experimental Medicine | volume = 213 | issue = 9 | pages = 1655–62 | date = August 2016 | pmid = 27481132 | pmc = 4995082 | doi = 10.1084/jem.20160061 | url = }} A second study using this mBSA model found that mBSA-treated mouse knee joints developed hyperalgesia and high numbers of inflammation-inducing neutrophils whereas the mBSA-treated joints of SUCNR1 gene knockout mice did not develop hyperalgesia and had significantly fewer neutrophils.{{cite journal | vauthors = Saraiva AL, Veras FP, Peres RS, Talbot J, de Lima KA, Luiz JP, Carballido JM, Cunha TM, Cunha FQ, Ryffel B, Alves-Filho JC | title = Succinate receptor deficiency attenuates arthritis by reducing dendritic cell traffic and expansion of Th17 cells in the lymph nodes | journal = FASEB Journal| volume = 32| issue = 12| pages = 6550–6558 | date = June 2018 | pmid = 29894669 | doi = 10.1096/fj.201800285 | doi-access = free | url = }} Rheumatoid arthritis is an autoimmune arthritis characterized by symmetric arthritis typically involving the small joints of the hands and feet but also commonly involving arthritis in larger joints and inflammation in a wide range of other tissues such as the lung, gastrointestinal tract, heart (e.g., dysfunction of the heart's microvasculature), and oral cavity.{{cite journal | vauthors = Gravallese EM, Firestein GS | title = Rheumatoid Arthritis - Common Origins, Divergent Mechanisms | journal = The New England Journal of Medicine | volume = 388 | issue = 6 | pages = 529–542 | date = February 2023 | pmid = 36780677 | doi = 10.1056/NEJMra2103726 | s2cid = 256721972 | url = }} Patients with rheumatoid arthritis have high levels of succinate in the synovial fluid of their inflamed joins and increased numbers of SUCNR1-expressing dendritic cells in the synovial membranes of these joints as well as some lymph nodes. These findings suggest that the succinate-induced activation of SUCNR1 contributes to the development of at least one from of arthritis in mice and may play a similar role in human rheumatoid arthritis. The studies also support further studies to determine if activated SUCNR1 promotes human rheumatoid arthritis.

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Category:G protein-coupled receptors