Skip to main content

Advertisement

Log in

Metabolic Nano-Machines: Extracellular Vesicles Containing Active Enzymes and Their Contribution to Liver Diseases

  • State of the Science: Role of Exosomes in Human Disease (A Clayton, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

The field of extracellular vesicles is growing exponentially because of the important role that these extracellular organelles had on cell to cell communication, triggering a large number of review compilations focusing on different aspects of their biology. Although their importance as effectors or potential biomarkers is well covered, the highlight of extracellular vesicles as carriers of active enzymes which have the capability to transform the surrounding media is less covered by bibliographic studies. In the present review, we focus our attention on enzymatic activity carried by vesicles, with special attention on their contribution to liver conditions.

Recent Findings

Extracellular vesicles are circulating membrane-bound entities, characterized by a specific cargo. This cargo depends on the parental cell and the stimulus that triggers their release. Interestingly, the cargo includes active enzymes which had the ability of transforming the extracellular environment. Among them, extracellular vesicles derived from hepatocytes harbor specific liver enzymes that may cause an impact in the surrounds and target cells.

Summary

In this review, we summarize different active enzymes described in extracellular vesicles and we focus on enzymatic activities associated to liver damage. Since their release increases under liver damage conditions, their activity impact could play a role in the pathogenesis of liver and liver-associated diseases. Numerous examples in different liver conditions provided evidence of the potential of extracellular vesicles as therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Vallabhaneni KC, Penfornis P, Dhule S, Guillonneau F, Adams KV, Mo YY, et al. Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget. 2015;6(7):4953–67.

    PubMed  Google Scholar 

  2. Abels ER, Breakefield XO. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol. 2016;36(3):301–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, J. Geuze H. Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol. 2000;165(3):1259–65.

    CAS  PubMed  Google Scholar 

  4. Masyuk AI, Masyuk TV, Larusso NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. J Hepatol. 2013;59(3):621–5.

    CAS  PubMed  Google Scholar 

  5. Holme PA, Solum NO, Brosstad F, Egberg N, Lindahl TL. Stimulated Glanzmann's thrombasthenia platelets produced microvesicles. Microvesiculation correlates better to exposure of procoagulant surface than to activation of GPIIb-IIIa. Thromb Haemost. 1995;74(6):1533–40.

    CAS  PubMed  Google Scholar 

  6. Kalra H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012;10(12):p. e1001450.

    Google Scholar 

  7. Chargaff E, West R. The biological significance of the thromboplastic protein of blood. J Biol Chem. 1946;166(1):189–97.

    CAS  PubMed  Google Scholar 

  8. Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 1969;41(1):59–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.

    CAS  Google Scholar 

  10. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20(5):847–56.

    CAS  PubMed  Google Scholar 

  11. Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983;97(2):329–39.

    CAS  PubMed  Google Scholar 

  12. Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33(3):967–78.

    CAS  PubMed  Google Scholar 

  13. Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol. 1984;35(2):256–63.

    CAS  PubMed  Google Scholar 

  14. Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol. 1985;101(3):942–8.

    CAS  PubMed  Google Scholar 

  15. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–72.

    CAS  PubMed  Google Scholar 

  16. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594–600.

    CAS  PubMed  Google Scholar 

  17. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Thery C, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.

    PubMed  PubMed Central  Google Scholar 

  19. Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, et al. Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol. 2005;174(11):7268–77.

    CAS  PubMed  Google Scholar 

  20. Pena-Altamira LE, et al. Release of soluble and vesicular purine nucleoside phosphorylase from rat astrocytes and microglia induced by pro-inflammatory stimulation with extracellular ATP via P2X7 receptors. Neurochem Int. 2018;115:37–49.

    CAS  PubMed  Google Scholar 

  21. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71(11):3792–801.

    CAS  PubMed  Google Scholar 

  22. Sato K, et al. Exosomes in liver pathology. J Hepatol. 2016;65(1):213–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820(7):940–8.

    CAS  Google Scholar 

  24. De Toro J, et al. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol. 2015;6:203.

    PubMed  PubMed Central  Google Scholar 

  25. San Lucas FA, Allenson K, Bernard V, Castillo J, Kim DU, Ellis K, et al. Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann Oncol. 2016;27(4):635–41.

    CAS  PubMed  Google Scholar 

  26. Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481–92.

    PubMed  Google Scholar 

  27. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22(6):845–54.

    CAS  PubMed  Google Scholar 

  28. Deng F, Magee N, Zhang Y. Decoding the role of extracellular vesicles in liver diseases. Liver Res. 2017;1(3):147–55.

    PubMed  PubMed Central  Google Scholar 

  29. Bruno S, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Royo F, Falcon-Perez JM. Liver extracellular vesicles in health and disease. J Extracell Vesicles. 2012;1.

    CAS  Google Scholar 

  31. Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res. 2008;7(12):5157–66.

    CAS  PubMed  Google Scholar 

  32. Herrera MB, et al. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14(6B):1605–18.

    CAS  PubMed  Google Scholar 

  33. Rodriguez-Suarez E, et al. Quantitative proteomic analysis of hepatocyte-secreted extracellular vesicles reveals candidate markers for liver toxicity. J Proteome. 2014;103:227–40.

    CAS  Google Scholar 

  34. Momen-Heravi F, Saha B, Kodys K, Catalano D, Satishchandran A, Szabo G. Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med. 2015;13:261.

    PubMed  Google Scholar 

  35. Johnstone RM, et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412–20.

    CAS  PubMed  Google Scholar 

  36. Rieu S, et al. Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. Eur J Biochem. 2000;267(2):583–90.

    CAS  PubMed  Google Scholar 

  37. Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, et al. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol. 2008;79(1):12–7.

    CAS  PubMed  Google Scholar 

  38. Cantin R, Diou J, Bélanger D, Tremblay AM, Gilbert C. Discrimination between exosomes and HIV-1: purification of both vesicles from cell-free supernatants. J Immunol Methods. 2008;338(1–2):21–30.

    CAS  PubMed  Google Scholar 

  39. Johnstone RM, Bianchini A, Teng K. Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood. 1989;74(5):1844–51.

    CAS  PubMed  Google Scholar 

  40. Kim DK, Kang B, Kim OY, Choi DS, Lee J, Kim SR, et al. EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles. J Extracell Vesicles. 2013;2(2).

    Google Scholar 

  41. Kim J, Hong SW, Kim S, Kim D, Hur DY, Jin DH, et al. Cyclooxygenase-2 expression is induced by celecoxib treatment in lung cancer cells and is transferred to neighbor cells via exosomes. Int J Oncol. 2018;52(2):613–20.

    CAS  PubMed  Google Scholar 

  42. Saadi E, Tal S, Barki-Harrington L. Substrate-inactivated cyclooxygenase-2 is disposed of by exosomes through the ER-Golgi pathway. Biochem J. 2018;475(19):3141–51.

    CAS  PubMed  Google Scholar 

  43. Merendino AM, Bucchieri F, Campanella C, Marcianò V, Ribbene A, David S, et al. Hsp60 is actively secreted by human tumor cells. PLoS One. 2010;5(2):e9247.

    PubMed  Google Scholar 

  44. de Jong OG, van Balkom BWM, Gremmels H, Verhaar MC. Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2. J Cell Mol Med. 2016;20(2):342–50.

    PubMed  Google Scholar 

  45. Hakulinen J, Sankkila L, Sugiyama N, Lehti K, Keski-Oja J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J Cell Biochem. 2008;105(5):1211–8.

    CAS  PubMed  Google Scholar 

  46. Iraci N, Gaude E, Leonardi T, Costa ASH, Cossetti C, Peruzzotti-Jametti L, et al. Extracellular vesicles are independent metabolic units with asparaginase activity. Nat Chem Biol. 2017;13(9):951–5.

    CAS  PubMed  Google Scholar 

  47. Stewart AJ, Leong DTK, Farquharson C. PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization. FASEB J. 2018;32(1):20–5.

    CAS  PubMed  Google Scholar 

  48. Quesada A, Segarra AB, Montoro-Molina S, de Gracia MC, Osuna A, O’Valle F, et al. Glutamyl aminopeptidase in microvesicular and exosomal fractions of urine is related with renal dysfunction in cisplatin-treated rats. PLoS One. 2017;12(4):e0175462.

    PubMed  Google Scholar 

  49. Liu T, Mendes DE, Berkman CE. Functional prostate-specific membrane antigen is enriched in exosomes from prostate cancer cells. Int J Oncol. 2014;44(3):918–22.

    CAS  PubMed  Google Scholar 

  50. Clayton A, al-Taei S, Webber J, Mason MD, Tabi Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol. 2011;187(2):676–83.

    CAS  Google Scholar 

  51. Conde-Vancells J, Gonzalez E, Lu SC, Mato JM, Falcon-Perez JM. Overview of extracellular microvesicles in drug metabolism. Expert Opin Drug Metab Toxicol. 2010;6(5):543–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Royo F, Palomo L, Mleczko J, Gonzalez E, Alonso C, Martínez I, et al. Metabolically active extracellular vesicles released from hepatocytes under drug-induced liver-damaging conditions modify serum metabolome and might affect different pathophysiological processes. Eur J Pharm Sci. 2017;98:51–7.

    CAS  PubMed  Google Scholar 

  53. Royo F, Moreno L, Mleczko J, Palomo L, Gonzalez E, Cabrera D, et al. Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism. Sci Rep. 2017;7:42798.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Herrera Sanchez MB, et al. Extracellular vesicles from human liver stem cells restore argininosuccinate synthase deficiency. Stem Cell Res Ther. 2017;8(1):176.

    PubMed  PubMed Central  Google Scholar 

  55. Palomo L, et al. Abundance of cytochromes in hepatic extracellular vesicles is altered by drugs related with drug-induced liver injury. Hepatol Commun. 2018;2(9):1064–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cho YE, Mezey E, Hardwick JP, Salem N Jr, Clemens DL, Song BJ. Increased ethanol-inducible cytochrome P450-2E1 and cytochrome P450 isoforms in exosomes of alcohol-exposed rodents and patients with alcoholism through oxidative and endoplasmic reticulum stress. Hepatol Commun. 2017;1(7):675–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Yao J, Zheng J, Cai J, Zeng K, Zhou C, Zhang J, et al. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 2019;33(2):1695–710.

    CAS  PubMed  Google Scholar 

  58. Lin M, Liao W, Dong M, Zhu R, Xiao J, Sun T, et al. Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide. FEBS J. 2018;285(20):3835–48.

    CAS  PubMed  Google Scholar 

  59. Nojima H, Freeman CM, Schuster RM, Japtok L, Kleuser B, Edwards MJ, et al. Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate. J Hepatol. 2016;64(1):60–8.

    CAS  PubMed  Google Scholar 

  60. Caldwell RB, Toque HA, Narayanan SP, Caldwell RW. Arginase: an old enzyme with new tricks. Trends Pharmacol Sci. 2015;36(6):395–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: a multifaceted enzyme important in health and disease. Physiol Rev. 2018;98(2):641–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bailey WJ, Holder D, Patel H, Devlin P, Gonzalez RJ, Hamilton V, et al. A performance evaluation of three drug-induced liver injury biomarkers in the rat: alpha-glutathione S-transferase, arginase 1, and 4-hydroxyphenyl-pyruvate dioxygenase. Toxicol Sci. 2012;130(2):229–44.

    CAS  PubMed  Google Scholar 

  63. Jiang M, Ding Y, Su Y, Hu X, Li J, Zhang Z. Arginase-flotillin interaction brings arginase to red blood cell membrane. FEBS Lett. 2006;580(28–29):6561–4.

    CAS  PubMed  Google Scholar 

  64. Royo F, Cossío U, Ruiz de Angulo A, Llop J, Falcon-Perez JM. Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice. Nanoscale. 2019;11(4):1531–7.

    CAS  PubMed  Google Scholar 

  65. Silberman A, et al. Acid-induced downregulation of ASS1 contributes to the maintenance of intracellular pH in cancer. Cancer Res. 2019;79(3):518–33.

    CAS  PubMed  Google Scholar 

  66. Moren L, et al. Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM. BMC Cancer. 2018;18(1):167.

    PubMed  PubMed Central  Google Scholar 

  67. Ratner S. Enzymes of arginine and urea synthesis. Adv Enzymol Relat Areas Mol Biol. 1973;39:1–90.

    CAS  PubMed  Google Scholar 

  68. Beaudet AL, et al. The human argininosuccinate synthetase locus and citrullinemia. Adv Hum Genet. 1986;15:161–96 291–2.

    CAS  PubMed  Google Scholar 

  69. Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem. 1958;233(3):702–5.

    CAS  PubMed  Google Scholar 

  70. Tenhunen J, Ulmanen I. Production of rat soluble and membrane-bound catechol O-methyltransferase forms from bifunctional mRNAs. Biochem J. 1993;296(Pt 3):595–600.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kanasaki M, et al. Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice. Sci Rep. 2017;7(1):7927.

    PubMed  PubMed Central  Google Scholar 

  72. Kring SI, et al. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes. PLoS One. 2009;4(8):e6696.

    PubMed  PubMed Central  Google Scholar 

  73. Bastos P, Gomes T, Ribeiro L. Catechol-O-methyltransferase (COMT): an update on its role in cancer, neurological and cardiovascular diseases. Rev Physiol Biochem Pharmacol. 2017;173:1–39.

    CAS  PubMed  Google Scholar 

  74. Sak K. The Val158Met polymorphism in COMT gene and cancer risk: role of endogenous and exogenous catechols. Drug Metab Rev. 2017;49(1):56–83.

    CAS  PubMed  Google Scholar 

  75. Kambur O, Mannisto PT. Catechol-O-methyltransferase and pain. Int Rev Neurobiol. 2010;95:227–79.

    CAS  PubMed  Google Scholar 

  76. Leehr EJ, Schag K, Brückmann C, Plewnia C, Zipfel S, Nieratschker V, et al. A putative association of COMT Val(108/158)met with impulsivity in binge eating disorder. Eur Eat Disord Rev. 2016;24(2):169–73.

    PubMed  Google Scholar 

  77. Lin CH, et al. Depression and catechol-O-methyltransferase (COMT) genetic variants are associated with pain in Parkinson's disease. Sci Rep. 2017;7(1):6306.

    PubMed  PubMed Central  Google Scholar 

  78. Casal E, et al. A novel sensitive method to measure catechol-O-methyltransferase activity unravels the presence of this activity in extracellular vesicles released by rat hepatocytes. Front Pharmacol. 2016;7:501.

    PubMed  PubMed Central  Google Scholar 

  79. Hu Z, Lausted C, Yoo H, Yan X, Brightman A, Chen J, et al. Quantitative liver-specific protein fingerprint in blood: a signature for hepatotoxicity. Theranostics. 2014;4(2):215–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Satoh T, Hosokawa M. The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol. 1998;38:257–88.

    CAS  PubMed  Google Scholar 

  81. Sanghani SP, Quinney SK, Fredenburg TB, Davis WI, Murry DJ, Bosron WF. Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. Drug Metab Dispos. 2004;32(5):505–11.

    CAS  PubMed  Google Scholar 

  82. Yang L, et al. A unique role of carboxylesterase 3 (Ces3) in beta-adrenergic signaling stimulated thermogenesis. Diabetes. 2019.

  83. Dominguez, E., et al., Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes. Nat Chem Biol, 2014. 10(2): p. 113–21.

    PubMed  PubMed Central  Google Scholar 

  84. Lian J, et al. Ces3/TGH deficiency attenuates steatohepatitis. Sci Rep. 2016;6:p. 25747.

    Google Scholar 

  85. Huang TL, Villalobos SA, Hammock BD. Effect of hepatotoxic doses of paracetamol and carbon tetrachloride on the serum and hepatic carboxylesterase activity in mice. J Pharm Pharmacol. 1993;45(5):458–65.

    CAS  PubMed  Google Scholar 

  86. Lian J, Quiroga AD, Li L, Lehner R. Ces3/TGH deficiency improves dyslipidemia and reduces atherosclerosis in Ldlr(−/−) mice. Circ Res. 2012;111(8):982–90.

    CAS  PubMed  Google Scholar 

  87. Estabrook RW. A passion for P450s (remembrances of the early history of research on cytochrome P450). Drug Metab Dispos. 2003;31(12):1461–73.

    CAS  PubMed  Google Scholar 

  88. Testa B, Kramer SD. The biochemistry of drug metabolism—an introduction: part 3. Reactions of hydrolysis and their enzymes. Chem Biodivers. 2007;4(9):2031–122.

    CAS  PubMed  Google Scholar 

  89. Yamashita YI, et al. Idiosyncratic drug-induced liver injury: a short review. Hepatol Commun. 2017, 1(6):494–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004;44:27–42.

    CAS  PubMed  Google Scholar 

  91. Buckpitt AR, Warren DL. Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extrahepatic tissues in vivo. J Pharmacol Exp Ther. 1983;225(1):8–16.

    CAS  PubMed  Google Scholar 

  92. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112.

    CAS  PubMed  Google Scholar 

  93. Sun J, et al. Association of KCTD10, MVK, and MMAB polymorphisms with dyslipidemia and coronary heart disease in Han Chinese population. Lipids Health Dis. 2016;15(1):171.

    PubMed  PubMed Central  Google Scholar 

  94. Wang P, et al. Association between MnSOD Val16Ala polymorphism and cancer risk: evidence from 33,098 cases and 37,831 controls. Dis Markers. 2018;2018:p. 3061974.

    Google Scholar 

  95. Yahya MJ, et al. CNDP1, NOS3, and MnSOD polymorphisms as risk factors for diabetic nephropathy among type 2 diabetic patients in Malaysia. J Nutr Metab. 2019;2019:8736215.

    PubMed  PubMed Central  Google Scholar 

  96. Yarana C, Carroll D, Chen J, Chaiswing L, Zhao Y, Noel T, et al. Extracellular vesicles released by cardiomyocytes in a doxorubicin-induced cardiac injury mouse model contain protein biomarkers of early cardiac injury. Clin Cancer Res. 2018;24(7):1644–53.

    CAS  PubMed  Google Scholar 

  97. Eltzschig HK, Eckle T. Ischemia and reperfusion—from mechanism to translation. Nat Med. 2011;17(11):1391–401.

    CAS  PubMed  Google Scholar 

  98. Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci. 2005;118(Pt 20):4605–12.

    CAS  PubMed  Google Scholar 

  99. Hannun YA, Obeid LM. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem. 2002;277(29):25847–50.

    CAS  PubMed  Google Scholar 

  100. Garcia-Ruiz C, Mato JM, Vance D, Kaplowitz N, Fernández-Checa JC. Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways. J Hepatol. 2015;62(1):219–33.

    CAS  PubMed  Google Scholar 

  101. Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013;13(1):51–65.

    CAS  PubMed  Google Scholar 

  102. Levade T, Salvayre R, Douste-Blazy L. Sphingomyelinases and Niemann–Pick disease. J Clin Chem Clin Biochem. 1986;24(4):205–20.

    CAS  PubMed  Google Scholar 

  103. Riboni L, Campanella R, Bassi R, Villani R, Gaini SM, Martinelli-Boneschi F, et al. Ceramide levels are inversely associated with malignant progression of human glial tumors. Glia. 2002;39(2):105–13.

    PubMed  Google Scholar 

  104. Yabu T, Imamura S, Yamashita M, Okazaki T. Identification of Mg2+-dependent neutral sphingomyelinase 1 as a mediator of heat stress-induced ceramide generation and apoptosis. J Biol Chem. 2008;283(44):29971–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Ikeda H, Satoh H, Yanase M, Inoue Y, Tomiya T, Arai M, et al. Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of rho via Edg-5. Gastroenterology. 2003;124(2):459–69.

    CAS  PubMed  Google Scholar 

  106. Ikeda H, Watanabe N, Ishii I, Shimosawa T, Kume Y, Tomiya T, et al. Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J Lipid Res. 2009;50(3):556–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Corcoran CA, He Q, Ponnusamy S, Ogretmen B, Huang Y, Sheikh MS. Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Mol Cancer Res. 2008;6(5):795–807.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Casella G, Colombo F, Finardi A, Descamps H, Ill-Raga G, Spinelli A, et al. Extracellular vesicles containing IL-4 modulate Neuroinflammation in a mouse model of multiple sclerosis. Mol Ther. 2018;26(9):2107–18.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Spanish Ministry of Economy and Competitiveness MINECO (SAF2015-66312 and RTI2018-094969-B-I00) and the Ramon Areces Foundation (FRA-17-JMF). We thank MINECO for the REDIEX (Spanish Excellence Network in Exosomes) and the Severo Ochoa Excellence Accreditation (SEV-2016-0644).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Félix Royo or Juan M. Falcón-Pérez.

Ethics declarations

Conflict of Interest

M.A.A., F.R., and J.M.F.-P. declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on State of the Science: Role of Exosomes in Human Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Angulo, M.A., Royo, F. & Falcón-Pérez, J.M. Metabolic Nano-Machines: Extracellular Vesicles Containing Active Enzymes and Their Contribution to Liver Diseases. Curr Pathobiol Rep 7, 119–127 (2019). https://doi.org/10.1007/s40139-019-00197-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40139-019-00197-3

Keywords

Navigation