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Succinate As A Regulator Of Hepatic Stellate Cells In Liver Fibrosis

Eun-Hee Cho
Published 2018 · Chemistry, Medicine

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The rapid increase of obesity rates worldwide is associated with chronic liver injury due to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Chronic liver inflammation drives hepatic fibrosis, which is a highly conserved and coordinated protective response to tissue injury, and is a reversible process. Hepatocytes, immune cells, and hepatic stellate cells (HSCs) have been identified as key players in the mechanisms of hepatic fibrosis and inflammation. During the last decade, succinate, an intermediate of the tricarboxylic acid cycle in mitochondrial ATP production, has emerged as an important signaling molecule in various diseases. Succinate acts as an extracellular ligand for G-protein coupled receptor 91, also known as succinate receptor 1, which is mainly expressed in the kidney, heart, liver, immune cells, and retinal cells, suggesting a widespread function in cellular metabolism. Furthermore, succinate stabilizes hypoxia-inducible factor-1α in immune cells and tumors as a signaling molecule, and has been shown to post-translationally modify proteins. This review summarizes the recent evidence pointing to an additional role of succinate in profibrotic signaling, along with its downstream signaling pathways, and updates the current state of knowledge on the role of succinate in liver fibrosis through its action on HSCs. Further focus on this link can help identify succinate, its receptor, and its downstream signaling molecules as new targets for the treatment of liver fibrosis.
This paper references
10.1172/JCI1018
Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.
J. Iredale (1998)
10.1093/CLINCHEM/47.11.1993
Analysis of dicarboxylic acids by tandem mass spectrometry. High-throughput quantitative measurement of methylmalonic acid in serum, plasma, and urine.
M. Kushnir (2001)
10.1083/jcb.200205057
The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide–dependent deacetylase
Björn Schwer (2002)
10.1073/pnas.222538099
SIRT3, a human SIR2 homologue, is an NAD- dependent deacetylase localized to mitochondria
P. Onyango (2002)
10.2741/887
Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell.
E. Gäbele (2003)
10.1038/nature02488
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
W. He (2004)
10.1172/jci24282
Liver fibrosis.
R. Bataller (2005)
10.3748/WJG.V12.I46.7413
Role of Kupffer cells in the pathogenesis of liver disease.
G. Kolios (2006)
10.1111/j.1440-1746.2006.04584.x
Hepatic stellate cells and the reversal of fibrosis
T. Kisseleva (2006)
10.1016/J.JHEP.2007.03.016
Succinate is a paracrine signal for liver damage.
P. R. Correa (2007)
10.1016/J.AMJHYPER.2007.05.010
Circulating succinate is elevated in rodent models of hypertension and metabolic disease.
N. Sadagopan (2007)
10.1038/ni.1657
Triggering the succinate receptor GPR91 on dendritic cells enhances immunity
T. Rubic (2008)
10.1038/nm.1873
The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis
P. Sapieha (2008)
10.1053/j.gastro.2008.03.003
Mechanisms of hepatic fibrogenesis.
S. Friedman (2008)
10.1681/ASN.2008070740
Activation of the succinate receptor GPR91 in macula densa cells causes renin release.
Sarah L. Vargas (2009)
10.1016/j.mito.2010.03.001
Succinate dehydrogenase - Assembly, regulation and role in human disease.
J. Rutter (2010)
10.1021/bi901627u
Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
H. Cimen (2010)
10.1016/j.bmcl.2011.04.091
Discovery of a potent and selective small molecule hGPR91 antagonist.
D. Bhuniya (2011)
10.1016/j.bpg.2011.02.005
Mechanisms of hepatic fibrogenesis.
Ursula E. Lee (2011)
10.1016/j.molcel.2011.07.019
SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.
M. Hirschey (2011)
10.3389/fendo.2012.00022
The Succinate Receptor as a Novel Therapeutic Target for Oxidative and Metabolic Stress-Related Conditions
A. C. Ariza (2012)
10.1172/JCI66369
Hepatic stellate cells in liver development, regeneration, and cancer.
Chunyue Yin (2013)
10.1016/j.molcel.2013.06.001
SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways.
Jeongsoon Park (2013)
10.1016/j.biopha.2012.10.002
Clearance of activated stellate cells for hepatic fibrosis regression: molecular basis and translational potential.
Desong Kong (2013)
10.1016/j.exer.2013.01.011
Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91.
J. Hu (2013)
10.1016/j.tcb.2013.11.008
Succinate: a metabolic signal in inflammation.
E. Mills (2014)
10.1016/j.jss.2014.03.036
Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis.
F. J. Bohanon (2014)
10.2337/db14-0346
Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity
K. McCreath (2014)
10.1038/nri3623
Liver fibrosis and repair: immune regulation of wound healing in a solid organ
A. Pellicoro (2014)
10.1186/s12964-014-0078-2
Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
C. J. Aguiar (2014)
10.1016/j.bbrc.2015.06.023
Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells.
Y. H. Li (2015)
10.1016/j.jhep.2015.02.039
Hepatic fibrosis: Concept to treatment.
C. Trautwein (2015)
10.1084/jem.20160061
GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis
A. Littlewood-Evans (2016)
10.1016/j.metabol.2015.12.012
The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).
E. Buzzetti (2016)
10.1186/s12964-016-0126-1
GPR91: expanding the frontiers of Krebs cycle intermediates
Matheus de Castro Fonseca (2016)
10.1074/jbc.M115.692244
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*
Y. H. Li (2016)
10.1371/journal.pone.0147597
The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy
Lei Yang (2016)
10.1016/j.bpg.2017.04.005
Reversal of liver fibrosis: From fiction to reality.
M. E. Zoubek (2017)
10.1038/nrgastro.2017.38
Mechanisms of hepatic stellate cell activation
(2017)
10.1016/j.jhep.2017.02.026
Targeting hepatic macrophages to treat liver diseases.
F. Tacke (2017)
10.1074/jbc.M117.785022
Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain
Yuxun Zhang (2017)
10.1016/j.molmet.2017.09.005
Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91
Mette Trauelsen (2017)
10.1038/ncomms15621
Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis
Yuqi Guo (2017)
Succinate and its G-proteincoupled receptor stimulates osteoclastogenesis.Nat Commun
Y Guo (2017)
10.1016/j.bbrc.2018.01.106
Succinate induces hepatic fibrogenesis by promoting activation, proliferation, and migration, and inhibiting apoptosis of hepatic stellate cells.
S. Park (2018)
10.1371/journal.pone.0192146
LY2405319, an analog of fibroblast growth factor 21 ameliorates α-smooth muscle actin production through inhibition of the succinate—G-protein couple receptor 91 (GPR91) pathway in mice
Cong Thuc Le (2018)
10.1016/j.bbrc.2017.12.143
Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition.
Giang Nguyen (2018)



This paper is referenced by
10.3389/fphys.2021.624950
Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation
Itamar Dias (2021)
10.3390/ijms22136908
Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model
P. Staňková (2021)
10.4067/s0717-95022021000300732
Liver Structural Injury in Leptin-Deficient (ob/ob) Mice: Lipogenesis, Fibrogenesis, Inflammation, and Apoptosis
Fabiane Ferreira Martins (2021)
10.3390/ijms222212545
Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis
(2021)
10.3390/life11010069
Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Inseo Choi (2021)
10.1016/j.biopha.2021.112298
Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment.
Chengyuan Liang (2021)
Role of succinylation modification in thyroid cancer and breast cancer.
(2021)
10.3389/fphar.2021.759199
Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite
(2021)
10.1371/journal.pone.0231173
Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose
S. Piel (2020)
10.1021/acs.jmedchem.0c01020
Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure.
J. Velcicky (2020)
10.3389/fmolb.2020.00150
Association Between Succinate Receptor SUCNR1 Expression and Immune Infiltrates in Ovarian Cancer
Jiawen Zhang (2020)
10.1096/fj.202001037R
GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses
Xinyi Li (2020)
10.1016/j.dsx.2020.09.026
Pathophysiological mechanisms underlying MAFLD.
Mohammad Shafi Kuchay (2020)
10.3390/cancers12010068
TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma
S. Todisco (2019)
10.3390/cells9010024
Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis
O. Khomich (2019)
10.1038/s41586-019-1663-8
Structural basis of species-selective antagonist binding to the succinate receptor
M. Haffke (2019)
10.1038/s41586-019-1675-4
A glucose-sensing neuron pair regulates insulin and glucagon in Drosophila
Yangkyun Oh (2019)
10.3390/metabo9100227
Lomatogonium Rotatum for Treatment of Acute Liver Injury in Mice: A Metabolomics Study
Renhao Chen (2019)
10.3389/fcell.2018.00150
Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis
W. Hou (2018)
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