본문 바로가기
KERD
논문KCI 등재

Lactate: a multifunctional signaling molecule

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류의학일반

초록

Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

Abstract

Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

참고문헌 (99)

  1. Hsu PP, "Cancer cell metabolism : Warburg and beyond", Cell, 134, pp.703~707 (2008)
  2. Vander Heiden MG, "Understanding the Warburg effect : the metabolic requirements of cell proliferation", Science, 324, pp.1029~1033 (2009)
  3. Warburg O, "Versuche an überlebendem carcinom-gewebe", Klin Wochenschr, 2, pp.776~777 (1923)
  4. Warburg O, "On the origin of cancer cells", Science, 123, pp.309~314 (1956)
  5. Ferguson BS, "Lactate metabolism: historical context, prior misinterpretations, and current understanding", Eur J Appl Physiol, 118, pp.691~728 (2018)
  6. Hasegawa H, "Determination of serum D-lactic and L-lactic acids in normal subjects and diabetic patients by column-switching HPLC with pre-column fluorescence derivatization", Anal Bioanal Chem, 377, pp.886~891 (2003)
  7. Connor H, "Quantitative aspects of L(+)-lactate metabolism in human beings", Ciba Found Symp, 87, pp.214~234 (1982)
  8. Gladden LB, "Lactate metabolism : a new paradigm for the third millennium", J Physiol, 558, pp.5~30 (2004)
  9. de la Cruz-López KG, "Lactate in the regulation of tumor microenvironment and therapeutic approaches", Front Oncol, 9, pp.1143~ (2019)
  10. Valvona CJ, "The regulation and function of lactate dehydrogenase a : therapeutic potential in brain tumor", Brain Pathol, 26, pp.3~17 (2016)
  11. Fletcher WM, "Lactic acid in amphibian muscle", J Physiol, 35, pp.247~309 (1907)
  12. Hill AV, "Muscular exercise, lactic acid, and the supply and utilisation of oxygen", Proc R Soc Lond B Contain Pap Biol Character, 97, pp.84~138 (1924)
  13. Meyerhof O, "The chemistry of muscular contraction", Lancet, 216, pp.1415~1422 (1930)
  14. Wasserman K, "The anaerobic threshold measurement to evaluate exercise performance", Am Rev Respir Dis, 129(2 Pt 2), pp.S35~S40 (1984)
  15. Garcia-Alvarez M, "Sepsis-associated hyperlactatemia", Crit Care, 18, pp.503~ (2014)
  16. Kraut JA, "Lactic acidosis", N Engl J Med, 371, pp.2309~2319 (2014)
  17. Robergs RA, "Biochemistry of exercise-induced metabolic acidosis", Am J Physiol Regul Integr Comp Physiol, 287, pp.R502~R516 (2004)
  18. Feher JJ, "Quantitative human physiology: an introduction. 2.9 - ATP production I: glycolysis", pp.171~179 (2016), Elsevier Science Publishing
  19. Argiles A, "proteins and drugs", 6th International Symposium on Nephrology, Montecatini Terme, pp.1~8 (1990), Karger
  20. Levraut J, "Effect of continuous venovenous hemofiltration with dialysis on lactate clearance in critically ill patients", Crit Care Med, 25, pp.58~62 (1997)
  21. Cori CF, "The carbohydrate metabolism of tumors", J Biol Chem, 65, pp.397~405 (1925)
  22. Consoli A, "Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans", Am J Physiol, 259, pp.E677~E684 (1990)
  23. Miller BF, "Lactate and glucose interactions during rest and exercise in men : effect of exogenous lactate infusion", J Physiol, 544, pp.963~975 (2002)
  24. Brooks GA, "Comparative physiology and biochemistry: current topics and trends. Vol. A. Respiration-metabolism–circulation", pp.208~218 (1985), Springer-Verlag
  25. Brooks GA, "Anaerobic threshold : review of the concept and directions for future research", Med Sci Sports Exerc, 17, pp.22~34 (1985)
  26. Brooks GA, "Lactate production under fully aerobic conditions : the lactate shuttle during rest and exercise", Fed Proc, 45, pp.2924~2929 (1986)
  27. Brooks GA, "Lactate shuttles in nature", Biochem Soc Trans, 30, pp.258~264 (2002)
  28. Boussouar F, "Lactate and energy metabolism in male germ cells", Trends Endocrinol Metab, 15, pp.345~350 (2004)
  29. Ahmed K, "An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81", Cell Metab, 11, pp.311~319 (2010)
  30. Liu L, "The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE", D, 2017, pp.26, 719~737
  31. Johnson ML, "Transpulmonary pyruvate kinetics", Am J Physiol Regul Integr Comp Physiol, 301, pp.R769~R774 (2011)
  32. Brooks GA, "The science and translation of lactate shuttle theory", Cell Metab, 27, pp.757~785 (2018)
  33. Brooks GA, "Lactate as a fulcrum of metabolism", Redox Biol, 35, pp.101454~ (2020)
  34. lactate in humans during rest and exercise, "J Appl Physiol(1985)", 1986, 232~241
  35. Hashimoto T, "Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells : evidence of a mitochondrial lactate oxidation complex", Am J Physiol Endocrinol Metab, 290, pp.E1237~E1244 (2006)
  36. Stanley WC, "Myocardial lactate metabolism during exercise", Med Sci Sports Exerc, 23, pp.920~924 (1991)
  37. van Hall G, "Lactate kinetics in human tissues at rest and during exercise", Acta Physiol(Oxf), 199, pp.499~508 (2010)
  38. Pellerin L, "Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle", Dev Neurosci, 20, pp.291~299 (1998)
  39. Sun S, "Lactic acid: no longer an inert and end-product of glycolysis", Physiology(Bethesda), 32, pp.453~463 (2017)
  40. Halestrap AP, "The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation", Biochem J 1999;343 Pt, 343(Pt 2), pp.281~299 (1999)
  41. Srinivas SR, "Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates(SMCT2)", Biochem J, 392, pp.655~664 (2005)
  42. Haas R, "Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions", PLoS Biol, 13, pp.e1002202~ (2015)
  43. Liu C, "3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes", J Pharmacol Exp Ther, 341, pp.794~801 (2012)
  44. de Castro Abrantes H, "The lactate receptor HCAR1 modulates neuronal network activity through the activation of Gα and Gβγ subunits", J Neurosci, 39, pp.4422~4433 (2019)
  45. Ohno Y, "Lactate increases myotube diameter via activation of MEK", ERK pathway in C2C12 cells, 2018, pp.223, e13042~
  46. Roland CL, "Cell surface lactate receptor GPR81 is crucial for cancer cell survival", Cancer Res, 74, pp.5301~5310 (2014)
  47. Harun-Or-Rashid M, "Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma", J Neuroinflammation, 15, pp.313~ (2018)
  48. Hoque R, "Lactate reduces liver and pancreatic injury in Toll-like receptor-and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity", Gastroenterology, 146, pp.1763~1774 (2014)
  49. Brown TP, "Lactate", GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon, 2020, pp.206, 107451~
  50. Langin D, "Adipose tissue lipolysis revisited(again!) : lactate involvement in insulin antilipolytic action", Cell Metab, 11, pp.242~243 (2010)
  51. Liu C, "Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor", J Biol Chem, 284, pp.2811~2822 (2009)
  52. Khatib-Massalha E, "Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling", Nat Commun, 11, pp.3547~ (2020)
  53. Hu J, "The roles of GRP81 as a metabolic sensor and inflammatory mediator", J Cell Physiol, 235, pp.8938~8950 (2020)
  54. Otto AM, "Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism", Cancer Metab, 4, pp.5~ (2016)
  55. Racker E, "Bioenergetics and the problem of tumor growth", Am Sci, 60, pp.56~63 (1972)
  56. Bonnet S, "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth", Cancer Cell, 11, pp.37~51 (2007)
  57. DeBerardinis RJ, "We need to talk about the Warburg effect", Nat Metab, 2, pp.127~129 (2020)
  58. Semenza GL, "A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation", Mol Cell Biol, 12, pp.5447~5454 (1992)
  59. Pavlides S, "The reverse Warburg effect : aerobic glycolysis in cancer associated fibroblasts and the tumor stroma", Cell Cycle, 8, pp.3984~4001 (2009)
  60. De Saedeleer CJ, "Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells", PLoS One, 7, pp.e46571~ (2012)
  61. Ali MA, "Enhancement of hydroxyl radical generation in the Fenton reaction by alpha-hydroxy acid", Biochem Mol Biol Int, 46, pp.137~145 (1998)
  62. Kozlov AM, "Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts", Sci Rep, 10, pp.8388~ (2020)
  63. Luo W, "Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells", Oncotarget, 2, pp.551~556 (2011)
  64. Hayashi Y, "Hypoxia", pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer, 2019, pp.110, 1510~1517
  65. Chang CH, "Posttranscriptional control of T cell effector function by aerobic glycolysis", Cell, 153, pp.1239~1251 (2013)
  66. Peng M, "Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism", Science, 354, pp.481~484 (2016)
  67. Nolt B, "Lactate and Immunosuppression in Sepsis", Shock, 49, pp.120~125 (2018)
  68. Pucino V, "Lactate at the crossroads of metabolism, inflammation, and autoimmunity", Eur J Immunol, 47, pp.14~21 (2017)
  69. Hirschhaeuser F, "Lactate : a metabolic key player in cancer", Cancer Res, 71, pp.6921~6925 (2011)
  70. Hotchkiss RS, "Sepsis-induced immunosuppression : from cellular dysfunctions to immunotherapy", Nat Rev Immunol, 13, pp.862~874 (2013)
  71. Hotchkiss RS, "Immunosuppression in sepsis : a novel understanding of the disorder and a new therapeutic approach", Lancet Infect Dis, 13, pp.260~268 (2013)
  72. Fischer K, "Inhibitory effect of tumor cell-derived lactic acid on human T cells", Blood, 109, pp.3812~3819 (2007)
  73. Michalek RD, "Cutting edge : distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets", J Immunol, 186, pp.3299~3303 (2011)
  74. Wenes M, "Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis", Cell Metab, 24, pp.701~715 (2016)
  75. Certo M, "Lactate modulation of immune responses in inflammatory versus tumour microenvironments", Nat Rev Immunol, 21, pp.151~161 (2021)
  76. Nasi A, "Disarmed by density : a glycolytic break for immunostimulatory dendritic cells", Oncoimmunology, 2, pp.e26744~ (2013)
  77. Gottfried E, "Tumor-derived lactic acid modulates dendritic cell activation and antigen expression", Blood, 107, pp.2013~2021 (2006)
  78. Kelly B, "Metabolic reprogramming in macrophages and dendritic cells in innate immunity", Cell Res, 25, pp.771~784 (2015)
  79. Schlee M, "Discriminating self from non-self in nucleic acid sensing", Nat Rev Immunol, 16, pp.566~580 (2016)
  80. Ivashkiv LB, "The hypoxia-lactate axis tempers inflammation", Nat Rev Immunol, 20, pp.85~86 (2020)
  81. Yasukawa K, "The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity", J Biol Chem, 295, pp.444~457 (2020)
  82. Zhang W, "Lactate is a natural suppressor of RLR signaling by targeting MAVS", Cell, 178, pp.176~189 (2019)
  83. Prakash K, "Evidence for the implication of the histone code in building the genome structure", Biosystems, 164, pp.49~59 (2018)
  84. Zhang D, "Metabolic regulation of gene expression by histone lactylation", Nature, 574, pp.575~580 (2019)
  85. Hunt TK, "Anaerobic metabolism and wound healing : an hypothesis for the initiation and cessation of collagen synthesis in wounds", Am J Surg, 135, pp.328~332 (1978)
  86. Constant JS, "Lactate elicits vascular endothelial growth factor from macrophages : a possible alternative to hypoxia", Wound Repair Regen, 8, pp.353~360 (2000)
  87. Hunt TK, "Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms", Antioxid Redox Signal, 9, pp.1115~1124 (2007)
  88. Porporato PE, "Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice", Angiogenesis, 15, pp.581~592 (2012)
  89. Turnbaugh PJ, "The human microbiome project", Nature, 449, pp.804~810 (2007)
  90. Iraporda C, "Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells", Immunobiology, 220, pp.1161~1169 (2015)
  91. Iraporda C, "The role of lactate on the immunomodulatory properties of the nonbacterial fraction of kefir", Food Res Int, 62, pp.247~253 (2014)
  92. Iraporda C, "Biological activity of the non-microbial fraction of kefir : antagonism against intestinal pathogens", J Dairy Res, 84, pp.339~345 (2017)
  93. Teramae H, "The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract", Biomed Res, 31, pp.239~249 (2010)
  94. Clarke SF, "Exercise and associated dietary extremes impact on gut microbial diversity", Gut, 63, pp.1913~1920 (2014)
  95. Petersen LM, "Community characteristics of the gut microbiomes of competitive cyclists", Microbiome, 5, pp.98~ (2017)
  96. Scheiman J, "Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism", Nat Med, 25, pp.1104~1109 (2019)
  97. Nalos M, "Half-molar sodium lactate infusion improves cardiac performance in acute heart failure : a pilot randomised controlled clinical trial", Crit Care, 18, pp.R48~ (2014)
  98. Tassinari ID, "Lactate administration reduces brain injury and ameliorates behavioral outcomes following neonatal hypoxia-ischemia", Neuroscience, 448, pp.191~205 (2020)
  99. Zhang J, "Endothelial lactate controls muscle regeneration from ischemia by inducing m2-like macrophage polarization", Cell Metab, 31, pp.1136~1153 (2020)

관련 논문AI추천

이 간행물의 다른 논문 (12건)