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Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation.
Glia 2014; 62(3):477-90GLIA

Abstract

The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode.

Authors+Show Affiliations

Département de Physiologie, Université de Lausanne, Lausanne, Switzerland.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24375723

Citation

Rosafio, Katia, and Luc Pellerin. "Oxygen Tension Controls the Expression of the Monocarboxylate Transporter MCT4 in Cultured Mouse Cortical Astrocytes Via a Hypoxia-inducible Factor-1α-mediated Transcriptional Regulation." Glia, vol. 62, no. 3, 2014, pp. 477-90.
Rosafio K, Pellerin L. Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation. Glia. 2014;62(3):477-90.
Rosafio, K., & Pellerin, L. (2014). Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation. Glia, 62(3), pp. 477-90. doi:10.1002/glia.22618.
Rosafio K, Pellerin L. Oxygen Tension Controls the Expression of the Monocarboxylate Transporter MCT4 in Cultured Mouse Cortical Astrocytes Via a Hypoxia-inducible Factor-1α-mediated Transcriptional Regulation. Glia. 2014;62(3):477-90. PubMed PMID: 24375723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation. AU - Rosafio,Katia, AU - Pellerin,Luc, Y1 - 2013/12/21/ PY - 2013/10/16/received PY - 2013/11/29/revised PY - 2013/12/06/accepted PY - 2013/12/31/entrez PY - 2014/1/1/pubmed PY - 2015/1/6/medline KW - HIF-1α KW - MCT1 KW - energy metabolism KW - glycolysis KW - lactate SP - 477 EP - 90 JF - Glia JO - Glia VL - 62 IS - 3 N2 - The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/24375723/Oxygen_tension_controls_the_expression_of_the_monocarboxylate_transporter_MCT4_in_cultured_mouse_cortical_astrocytes_via_a_hypoxia_inducible_factor_1α_mediated_transcriptional_regulation_ L2 - https://doi.org/10.1002/glia.22618 DB - PRIME DP - Unbound Medicine ER -