lactate release
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2022 ◽  
Vol 12 ◽  
Author(s):  
Elidie Beard ◽  
Sylvain Lengacher ◽  
Sara Dias ◽  
Pierre J. Magistretti ◽  
Charles Finsterwald

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Shuyan Yang ◽  
Jing Wang ◽  
Rongjie Cheng ◽  
Bo Pang ◽  
Pengcheng Sun

Objective. Ovarian cancer (OC) represents the most lethal gynecologic malignancy globally. Over the decades, lncRNAs have been considered as study focuses due to their genome-wide expression through multiple mechanisms in which regulation of target gene transcription through interaction with transcription factors or epigenetic proteins is proven. In the present work, we focus on the functional role of LINC00035 in OC and its regulation mechanism on gene expression. Methods. We collected OC tissues and adjacent tumor-free tissues surgically resected from 67 OC patients. Cultured human OC cell lines SKOV3 and A2780 were assayed for their viability, migration, invasion, apoptosis in vitro using CCK-8 assays, transwell assays, and flow cytometric analysis. OC cell tumorigenesis in vivo was evaluated by mouse xenograft experiments. Glycolysis was evaluated by glucose uptake, lactate release, and ATP production assays. Luciferase activity assay, RNA immunoprecipitation (RIP), and RNA pull-down were performed to confirm the interactions among LINC00035, CEBPB, and SLC16A3. Results. LINC00035 was upregulated in OC tissues. LINC00035 knockdown was shown to repress SKOV3 and A2780 cell viability, migration, invasion, induce their apoptosis, and reduce glucose uptake, lactate release, and ATP production. LINC00035 could recruit CEBPB into the SLC16A3 promoter region, thus increasing the SLC16A3 transcription. SLC16A3 was upregulated in OC tissues. SLC16A3 knockdown exerted similar effects on SKOV3 and A2780 cells as LINC00035 knockdown. Rescue experiments found SLC16A3 overexpression resisting to LINC00035 knockdown on SKOV3 and A2780 cell viability, migration, invasion, apoptosis, glucose uptake, lactate release, and ATP production. Results also showed LINC00035 knockdown could inhibit OC cell tumorigenesis in vivo. Conclusion. The study reveals that LINC00035 promotes OC progression by regulating glycolysis and cell apoptosis through CEBPB-mediated transcriptional promotion of SLC16A3.


Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1000
Author(s):  
Frédéric Bouillaud ◽  
Noureddine Hammad ◽  
Laurent Schwartz

Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12092
Author(s):  
Tomasz Szkudelski ◽  
Karina Frąckowiak ◽  
Katarzyna Szkudelska

Hemin is an activator of heme oxygenase-1 (HO-1), an enzyme catalyzing heme degradation. Up-regulation of HO-1 is observed in response to various pathological conditions. Moreover, pharmacological activation of HO-1 is associated with numerous beneficial effects in the organism. Hemin was shown to exert, among other, anti-diabetic and anti-obesity properties. These effects are strongly linked with adipose tissue. However, the direct influence of hemin on metabolism of the fat cells have not been explored. The present study aimed to determine the short-term effects of hemin on metabolism of the primary rat adipocytes. We focused on processes directly related to lipid accumulation, such as lipogenesis and lipolysis. For this purpose, the isolated cells were subjected for 2 h to 40 µM hemin, and effects of this compound on insulin-stimulated glucose conversion to lipids, lactate release, lipolysis induced by various stimuli, and also on the antilipolytic action of insulin were determined. It was shown that hemin did not affect insulin-induced lipogenesis and lactate release. However, hemin significantly decreased lipolysis stimulated by epinephrine. The inhibitory effect of hemin on epinephrine-induced lipolysis was not abolished in the presence of SnMP, an inhibitor of HO-1, which suggests hemin action irrespective of this enzyme. Similar inhibitory effects on epinephrine-induced lipolysis were observed in the presence of 3 and 12 mM glucose. Moreover, hemin was shown to reduce epinephrine-induced lipolysis also when glucose was replaced by alanine or by succinate. Apart from changes in epinephrine action, it was found that the lipolytic response of the adipocytes to isoproterenol was also diminished by hemin. However, hemin failed to affect lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A), forskolin (an activator of adenylate cyclase), and also by DPCPX (an adenosine A1 receptor antagonist). Additionally, epinephrine-induced lipolysis was shown to be decreased by insulin, and this effect was deepened in the presence of hemin. These results indicate that short-term exposure of the adipocytes to hemin does not affect processes related to glucose metabolism, such as lipogenesis and lactate release. However, hemin was found to decrease the lipolytic response to adrenergic stimulation, which is associated with reduced lipid release from adipocytes. Moreover, our results indicate that hemin is also capable of diminishing the exaggerated lipolysis, which occurs in the presence of supraphysiological concentrations of glucose.


2021 ◽  
Vol 11 (8) ◽  
pp. 1056
Author(s):  
Barbara Vaccari Cardoso ◽  
Iliana Barrera ◽  
Valentina Mosienko ◽  
Alexander V. Gourine ◽  
Sergey Kasparov ◽  
...  

Astrocytes support and modulate neuronal activity through the release of L-lactate. The suggested roles of astrocytic lactate in the brain encompass an expanding range of vital functions, including central control of respiration and cardiovascular performance, learning, memory, executive behaviour and regulation of mood. Studying the effects of astrocytic lactate requires tools that limit the release of lactate selectively from astrocytes. Here, we report the validation in vitro of novel molecular constructs derived from enzymes originally found in bacteria, that when expressed in astrocytes, interfere with lactate handling. When lactate 2-monooxygenase derived from M. smegmatis was specifically expressed in astrocytes, it reduced intracellular lactate pools as well as lactate release upon stimulation. D-lactate dehydrogenase derived from L. bulgaricus diverts pyruvate towards D-lactate production and release by astrocytes, which may affect signalling properties of lactate in the brain. Together with lactate oxidase, which we have previously described, this set of transgenic tools can be employed to better understand astrocytic lactate release and its role in the regulation of neuronal activity in different behavioural contexts.


Author(s):  
Nikolaj Rittig ◽  
Niels K Aagaard ◽  
Elias Sundelin ◽  
Gerda E Villadsen ◽  
Thomas D Sandahl ◽  
...  

Glia ◽  
2021 ◽  
Author(s):  
Barbara Vaccari Cardoso ◽  
Alexey V. Shevelkin ◽  
Chantelle Terrillion ◽  
Olga Mychko ◽  
Valentina Mosienko ◽  
...  

2020 ◽  
Vol 2020 ◽  
pp. 1-24
Author(s):  
David G. Levitt ◽  
Joseph E. Levitt ◽  
Michael D. Levitt

Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer (“shuttle”) of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.


2020 ◽  
Vol 881 ◽  
pp. 173188
Author(s):  
Anna Hadjihambi ◽  
Anastassios Karagiannis ◽  
Shefeeq M. Theparambil ◽  
Gareth L. Ackland ◽  
Alexander V. Gourine

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