Lactate shuttle hypothesis

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The lactate shuttle hypothesis describes the movement of lactate intracellularly (within a cell) and intercellularly (between cells). The hypothesis is based on the observation that lactate is formed and utilized continuously in diverse cells under both anaerobic and aerobic conditions. [1] Further, lactate produced at sites with high rates of glycolysis and glycogenolysis can be shuttled to adjacent or remote sites including heart or skeletal muscles where the lactate can be used as a gluconeogenic precursor or substrate for oxidation. [2] The hypothesis was proposed by professor George Brooks of the University of California at Berkeley.

Contents

In addition to its role as a fuel source predominantly in the muscles, heart, brain, and liver, the lactate shuttle hypothesis also relates the role of lactate in redox signalling, gene expression, and lipolytic control. These additional roles of lactate have given rise to the term ‘lactormone’, pertaining to the role of lactate as a signalling hormone. [3]

Lactate and the Cori cycle

Prior to the formation of the lactate shuttle hypothesis, lactate had long been considered a byproduct resulting from glucose breakdown through glycolysis in times of anaerobic metabolism. [4] As a means of regenerating oxidized NAD+, lactate dehydrogenase catalyzes the conversion of pyruvate to lactate in the cytosol, oxidizing NADH to NAD+, regenerating the necessary substrate needed to continue glycolysis. Lactate is then transported from the peripheral tissues to the liver by means of the Cori Cycle where it is reformed into pyruvate through the reverse reaction using lactate dehydrogenase. By this logic, lactate was traditionally considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during times of anaerobic respiration. Lactate was essentially payment for ‘oxygen debt’ defined by Hill and Lupton as the ‘total amount of oxygen used, after cessation of exercise in recovery therefrom’. [5]

Cell-cell role of the lactate shuttle

In addition to Cori Cycle, the lactate shuttle hypothesis proposes complementary functions of lactate in multiple tissues. Contrary to the long-held belief that lactate is formed as a result of oxygen-limited metabolism, substantial evidence exists that suggests lactate is formed under both aerobic and anaerobic conditions, as a result of substrate supply and equilibrium dynamics. [6]

Tissue use (brain, heart, muscle)

During physical exertion or moderate intensity exercise lactate released from working muscle and other tissue beds is the primary fuel source for the heart, exiting the muscles through monocarboxylate transport protein (MCT). [7] This evidence is supported by an increased amount of MCT shuttle proteins in the heart and muscle in direct proportion to exertion as measured through muscular contraction. [8]

Furthermore, both neurons and astrocytes have been shown to express MCT proteins, suggesting that the lactate shuttle may be involved in brain metabolism. Astrocytes express MCT4, a low affinity transporter for lactate (Km = 35mM), suggesting its function is to export lactate produced by glycolysis. Conversely, neurons express MCT2, a high affinity transporter for lactate (Km = 0.7mM). Thus, it is hypothesized that the astrocytes produce lactate which is then taken up by the adjacent neurons and oxidized for fuel.

Intracellular role of the lactate shuttle

The lactate shuttle hypothesis also explains the balance of lactate production in the cytosol, via glycolysis or glycogenolysis, and lactate oxidation in the mitochondria (described below).

Peroxisomes

MCT2 transporters within the peroxisome function to transport pyruvate into the peroxisome where it is reduced by peroxisomal LDH (pLDH) to lactate. In turn, NADH is converted to NAD+, regenerating this necessary component for subsequent β-oxidation. Lactate is then shuttled out of the peroxisome via MCT2, where it is oxidized by cytoplasmic LDH (cLDH) to pyruvate, generating NADH for energy use and completing the cycle (see figure). [9]

Mitochondria

While the cytosolic fermentation pathway of lactate is well established, a novel feature of the lactate shuttle hypothesis is the oxidation of lactate in the mitochondria. Baba and Sherma (1971) were the first to identify the enzyme lactate dehydrogenase (LDH) in the mitochondrial inner membrane and matrix of rat skeletal and cardiac muscle. [10] Subsequently, LDH was found in the rat liver, kidney, and heart mitochondria. [11] It was also found that lactate could be oxidized as quickly as pyruvate in rat liver mitochondria. Because lactate can either be oxidized in the mitochondria (back to pyruvate for entry into the Krebs’ cycle, generating NADH in the process), or serve as a gluconeogenic precursor, the intracellular lactate shuttle has been proposed to account for the majority of lactate turnover in the human body (as evidenced by the slight increases in arterial lactate concentration). Brooks et al. confirmed this in 1999, when they found that lactate oxidation exceeded that of pyruvate by 10-40% in rat liver, skeletal, and cardiac muscle.

In 1990, Roth and Brooks found evidence for the facilitated transporter of lactate, monocarboxylate transport protein (MCT), in the sarcolemma vesicles of rat skeletal muscle. Later, MCT1 was the first of the MCT super family to be identified. [12] The first four MCT isoforms are responsible for pyruvate/lactate transport. MCT1 was found to be the predominant isoform in many tissues including skeletal muscle, neurons, erythrocytes, and sperm. [13] In skeletal muscle, MCT1 is found in the membranes of the sarcolemma, [12] peroxisome, [9] and mitochondria. [4] Because of the mitochondrial localization of MCT (to transport lactate into the mitochondria), LDH (to oxidize the lactate back to pyruvate), and COX (cytochrome c oxidase, the terminal element of the electron transport chain), Brooks et al. proposed the possibility of a mitochondrial lactate oxidation complex in 2006. This is supported by the observation that the ability of muscle cells to oxidize lactate was related to the density of mitochondria. [14] Furthermore, it was shown that training increases MCT1 protein levels in skeletal muscle mitochondria, and that corresponded with an increase in the ability of muscle to clear lactate from the body during exercise. [15] The affinity of MCT for pyruvate is greater than lactate, however two reactions will ensure that lactate will be present in concentrations that are orders of magnitude greater than pyruvate: first, the equilibrium constant of LDH(3.6 x 104) greatly favors the formation of lactate. Secondly, the immediate removal of pyruvate from the mitochondria (either via the Krebs’ cycle or gluconeogenesis) ensures that pyruvate is not present in great concentrations within the cell.

LDH isoenzyme expression is tissue-dependent. It was found that in rats, LDH-1 was the predominant form in the mitochondria of myocardium, but LDH-5 was predominant in the liver mitochondria. [4] It is suspected that this difference in isoenzyme is due to the predominant pathway the lactate will take - in liver it is more likely to be gluconeogenesis, whereas in the myocardium it is more likely to be oxidation. Despite these differences, it is thought that the redox state of the mitochondria dictates the ability of the tissues to oxidize lactate, not the particular LDH isoform.

Lactate as a signaling molecule: ‘lactormone’

Redox signaling

As illustrated by the peroxisomal intracellular lactate shuttle described above, the interconversion of lactate and pyruvate between cellular compartments plays a key role in the oxidative state of the cell. Specifically, the interconversion of NAD+ and NADH between compartments has been hypothesized to occur in the mitochondria. However, the evidence for this is lacking, as both lactate and pyruvate are quickly metabolized inside the mitochondria. However, the existence of the peroxisomal lactate shuttle suggests that this redox shuttle could exist for other organelles. [9]

Gene expression

Increased intracellular levels of lactate can act as a signalling hormone, inducing changes in gene expression that will upregulate genes involved in lactate removal. [16] These genes include MCT1, cytochrome c oxidase (COX), and other enzymes involved in the lactate oxidation complex. Additionally, lactate will increase levels of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC1-α), suggesting that lactate stimulates mitochondrial biogenesis. [1]

Control of lipolysis

In addition to the role of the lactate shuttle in supplying NAD+ substrate for β-oxidation in the peroxisomes, the shuttle also regulates FFA mobilization by controlling plasma lactate levels. Research has demonstrated that lactate functions to inhibit lipolysis in fat cells through activation of an orphan G-protein couple receptor (GPR81) that acts as a lactate sensor, inhibiting lipolysis in response to lactate . [17]

Role of lactate during exercise

As found by Brooks, et al., while lactate is disposed of mainly through oxidation and only a minor fraction supports gluconeogenesis, lactate is the main gluconeogenic precursor during sustained exercise. [1]

Brooks demonstrated in his earlier studies that little difference in lactate production rates were seen in trained and untrained subjects at equivalent power outputs. What was seen, however, was more efficient clearance rates of lactate in the trained subjects suggesting an upregulation of MCT protein. [1]

Local lactate use depends on exercise exertion. During rest, approximately 50% of lactate disposal take place through lactate oxidation whereas in time of strenuous exercise (50-75% VO2 max) approximately 75-80% of lactate is used by the active cell, indicating lactate’s role as a major contributor to energy conversion during increased exercise exertion.

Clinical significance

Highly malignant tumors rely heavily on anaerobic glycolysis (metabolism of glucose to lactic acid even under ample tissue oxygen; Warburg effect) and thus need to efflux lactic acid via MCTs to the tumor micro-environment to maintain a robust glycolytic flux and to prevent the tumor from being "pickled to death". [18] The MCTs have been successfully targeted in pre-clinical studies using RNAi [19] and a small-molecule inhibitor alpha-cyano-4-hydroxycinnamic acid (ACCA; CHC) to show that inhibiting lactic acid efflux is a very effective therapeutic strategy against highly glycolytic malignant tumors. [20] [21] [22]

In some tumor types, growth and metabolism relies on the exchange of lactate between glycolytic and rapidly respiring cells. This is of particular importance during tumor cell development when cells often undergo anaerobic metabolism, as described by the Warburg effect. Other cells in the same tumor may have access to or recruit sources of oxygen (via angiogenesis), allowing it to undergo aerobic oxidation. The lactate shuttle could occur as the hypoxic cells anaerobically metabolize glucose and shuttle the lactate via MCT to the adjacent cells capable of using the lactate as a substrate for oxidation. Investigation into how MCT-mediated lactate exchange in targeted tumor cells can be inhibited, therefore depriving cells of key energy sources, could lead to promising new chemotherapeutics. [23]

Additionally, lactate has been shown to be a key factor in tumor angiogenesis. Lactate promotes angiogenesis by upregulating HIF-1 in endothelial cells. Thus a promising target of cancer therapy is the inhibition of lactate export, through MCT-1 blockers, depriving developing tumors of an oxygen source. [24]

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Chemical reactions to release energy in cells

The citric acid cycle —also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Glycolysis</span> Catabolic pathway

Glycolysis is the metabolic pathway that converts glucose into pyruvate, and in most organisms, occurs in the liquid part of cells, the cytosol. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor, such as oxygen, to drive the bulk production of adenosine triphosphate (ATP), which contains energy. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into ATP, and then release waste products.

<span class="mw-page-title-main">Lactic acid</span> Group of stereoisomers

Lactic acid is an organic acid. It has a molecular formula CH3CH(OH)COOH. It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natural sources. Lactic acid is an alpha-hydroxy acid (AHA) due to the presence of a hydroxyl group adjacent to the carboxyl group. It is used as a synthetic intermediate in many organic synthesis industries and in various biochemical industries. The conjugate base of lactic acid is called lactate. The name of the derived acyl group is lactoyl.

Anaerobic glycolysis is the transformation of glucose to lactate when limited amounts of oxygen (O2) are available. Anaerobic glycolysis is only an effective means of energy production during short, intense exercise, providing energy for a period ranging from 10 seconds to 2 minutes. This is much faster than aerobic metabolism. The anaerobic glycolysis (lactic acid) system is dominant from about 10–30 seconds during a maximal effort. It replenishes very quickly over this period and produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules). The speed at which ATP is produced is about 100 times that of oxidative phosphorylation.

Digestion is the breakdown of carbohydrates to yield an energy-rich compound called ATP. The production of ATP is achieved through the oxidation of glucose molecules. In oxidation, the electrons are stripped from a glucose molecule to reduce NAD+ and FAD. NAD+ and FAD possess a high energy potential to drive the production of ATP in the electron transport chain. ATP production occurs in the mitochondria of the cell. There are two methods of producing ATP: aerobic and anaerobic. In aerobic respiration, oxygen is required. Using oxygen increases ATP production from 4 ATP molecules to about 30 ATP molecules. In anaerobic respiration, oxygen is not required. When oxygen is absent, the generation of ATP continues through fermentation. There are two types of fermentation: alcohol fermentation and lactic acid fermentation.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Pyruvate dehydrogenase complex</span> Three-enzyme complex responsible for pyruvate decarboxylation

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate.

In oncology, the Warburg effect is the observation that most cancer cells produce energy predominantly not through the 'usual' citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of 'aerobic glycolysis' consisting of a high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The precise mechanism and therapeutic implications of the Warburg effect, however, remain unclear.

<span class="mw-page-title-main">Warburg hypothesis</span> Hypothesis explaining cancer

The Warburg hypothesis, sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term Warburg effect in oncology describes the observation that cancer cells, and many cells grown in vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate production and mitochondrial respiration even in the presence of oxygen.

<span class="mw-page-title-main">Pyruvate dehydrogenase kinase</span> Class of enzymes

Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

<span class="mw-page-title-main">Glycerol phosphate shuttle</span>

The glycerol-3-phosphate shuttle is a mechanism used in skeletal muscle and the brain that regenerates NAD+ from NADH, a by-product of glycolysis. The NADH generated during glycolysis is found in the cytoplasm and must be transported into the mitochondria to enter the oxidative phosphorylation pathway. However, the inner mitochondrial membrane is impermeable to NADH and NAD+ and does not contain a transport system for these electron carriers. Either the glycerol-3-phosphate shuttle pathway or the malate-aspartate shuttle pathway, depending on the tissue of the organism, must be taken to transport cytoplasmic NADH into the mitochondria. The shuttle consists of the sequential activity of two proteins; Cytoplasmic glycerol-3-phosphate dehydrogenase (cGPD) transfers an electron pair from NADH to dihydroxyacetone phosphate (DHAP), forming glycerol-3-phosphate (G3P) and regenerating NAD+ needed to generate energy via glycolysis. The other protein, mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) catalyzes the oxidation of G3P by FAD, regenerating DHAP in the cytosol and forming FADH2 in the mitochondrial matrix. In mammals, its activity in transporting reducing equivalents across the mitochondrial membrane is considered secondary to the malate-aspartate shuttle.

<span class="mw-page-title-main">Lactate dehydrogenase</span> Class of enzymes

Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvate to lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.

<span class="mw-page-title-main">PDK2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

<span class="mw-page-title-main">Monocarboxylate transporter 4</span> Protein-coding gene in the species Homo sapiens

Monocarboxylate transporter 4 (MCT4) also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the SLC16A3 gene.

<span class="mw-page-title-main">Monocarboxylate transporter 1</span>

Monocarboxylate transporter 1 is a ubiquitous protein that in humans is encoded by the SLC16A1 gene. It is a proton coupled monocarboxylate transporter.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

The monocarboxylate transporters, or MCTs, are a family of proton-linked plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate, pyruvate, and ketones across biological membranes. MCTs are expressed in nearly every kind of cell.

The citrate-malate shuttle is a series of chemical reactions – commonly referred to as a biochemical cycle or system – that transports acetyl-CoA in the mitochondrial matrix across the inner and outer mitochondrial membrane for fatty acid synthesis. Mitochondria is enclosed in a double membrane. As the inner mitochondrial membrane is impermeable to acetyl-CoA, the shuttle system is essential to fatty acid synthesis in the cytosol. It plays an important role in the generation of lipids in the liver.

References

  1. 1 2 3 4 Brooks, G.A. (2009). "Cell-cell and intracellular lactate shuttles". The Journal of Physiology. 587 (23): 5591–5600. doi:10.1113/jphysiol.2009.178350. PMC   2805372 . PMID   19805739.
  2. ↑ Gladden, LB (Jul 1, 2004). "Lactate metabolism: a new paradigm for the third millennium". The Journal of Physiology. 558 (Pt 1): 5–30. doi:10.1113/jphysiol.2003.058701. PMC   1664920 . PMID   15131240.
  3. ↑ Gladden, LB (Mar 2008). "Current trends in lactate metabolism: introduction". Medicine & Science in Sports & Exercise. 40 (3): 475–6. doi: 10.1249/MSS.0b013e31816154c9 . PMID   18379209.
  4. 1 2 3 Brooks, G.A. (1999). "Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle". Proc Natl Acad Sci U S A. 96 (3): 1129–1134. Bibcode:1999PNAS...96.1129B. doi: 10.1073/pnas.96.3.1129 . PMC   15362 . PMID   9927705.
  5. ↑ Lupton, H. (1923). "An analysis of the effects of speed on the mechanical efficiency of human muscular movement". J Physiol. 57 (6): 337–353. doi:10.1113/jphysiol.1923.sp002072. PMC   1405479 . PMID   16993578.
  6. ↑ Brooks, G.A. (1998). "Mammalian fuel utilization during sustained exercise". Comp Biochem Physiol B. 120 (1): 89–107. doi:10.1016/s0305-0491(98)00025-x. PMID   9787780.
  7. ↑ Gertz, E.W. (1988). "Glucose and lactate interrelations during moderate-intensity exercise in humans". Metabolism. 37 (9): 850–858. doi:10.1016/0026-0495(88)90119-9. PMID   3138512.
  8. ↑ Bergersen, L.H. (2007). "Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle". Neuroscience. 145 (1): 11–19. doi:10.1016/j.neuroscience.2006.11.062. PMID   17218064. S2CID   45826369.
  9. 1 2 3 McClelland, G.B. (2003). "Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system?". Biochemical and Biophysical Research Communications. 304 (1): 130–135. doi:10.1016/s0006-291x(03)00550-3. PMID   12705896.
  10. ↑ Baba and Sharma (1971). "Histochemistry of lactic dehydrogenase in heart and pectoralis muscles of rat". J Cell Biol. 51 (3): 621–635. doi:10.1083/jcb.51.3.621. PMC   2108042 . PMID   5128351.
  11. ↑ Brandt, R.B. (1986). "Localization of L-lactate dehydrogenase in mitochondria". Arch Biochem Biophys. 246 (2): 673–80. doi:10.1016/0003-9861(86)90323-1. PMID   3518634.
  12. 1 2 Garcia, D.K. (1994). "Genetic diversity of cultured Penaeus vannamei shrimp using three molecular genetic techniques". Mol Mar Biol Biotechnol. 3 (5): 270–280. PMID   7881514.
  13. ↑ Price, N.T. (1998). "Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past". Biochemical Journal. 329 (2): 321–8. doi:10.1042/bj3290321. PMC   1219047 . PMID   9425115.
  14. ↑ Baldwin, K.M. (1978). "Lactate oxidative capacity in different types of muscle". Biochem Biophys Res Commun. 83 (1): 151–157. doi:10.1016/0006-291x(78)90410-2. PMID   697805.
  15. ↑ Dubouchaud, H. (2000). "Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle". Am J Physiol Endocrinol Metab. 278 (4): E571–9. doi:10.1152/ajpendo.2000.278.4.E571. PMID   10751188. S2CID   12809869.
  16. ↑ Hashimoto, T. (2008). "Mitochondrial lactate oxidation complex and an adaptive role for lactate production". Medicine & Science in Sports & Exercise. 40 (3): 486–494. doi: 10.1249/MSS.0b013e31815fcb04 . PMID   18379211.
  17. ↑ Liu, C. (2009). "Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81". The Journal of Biological Chemistry. 284 (5): 2811–22. doi: 10.1074/jbc.M806409200 . PMID   19047060.
  18. ↑ Mathupala SP, Colen CB, Parajuli P, Sloan AE (2007). "Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis (Review)". J Bioenerg Biomembr. 39 (1): 73–77. doi:10.1007/s10863-006-9062-x. PMC   3385854 . PMID   17354062.
  19. ↑ Mathupala SP, Parajuli P, Sloan AE (2004). "Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study". Neurosurgery. 55 (6): 1410–1419. doi:10.1227/01.neu.0000143034.62913.59. PMID   15574223. S2CID   46103144.
  20. ↑ Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47
  21. ↑ Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP (2006). "Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study". Neurosurgery. 59 (6): 1313–1323. doi:10.1227/01.NEU.0000249218.65332.BF. PMC   3385862 . PMID   17277695.
  22. ↑ Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP (2011). "Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study". Neoplasia. 13 (7): 620–632. doi:10.1593/neo.11134. PMC   3132848 . PMID   21750656.
  23. ↑ Sonveaux, P. (2008). "Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice". The Journal of Clinical Investigation. 118 (12): 3930–42. doi:10.1172/JCI36843. PMC   2582933 . PMID   19033663.
  24. ↑ De Saedeleer, C.J.; Copetti, T.; Porporato, P. E.; Verrax, J.; Feron, O.; Sonveaux, P. (2012). "Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells". PLOS ONE. 7 (10): e46571. Bibcode:2012PLoSO...746571D. doi: 10.1371/journal.pone.0046571 . PMC   3474765 . PMID   23082126.
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