Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes

Michael Dodd; Maria da Luz Sousa Fialho; Claudia N. Montes Aparico; Matthew Kerr; Kerstin N. Timm; Julian L. Griffin; Joost J.F.P. Luiken; Jan F.C. Glatz; Damian J Tyler; Lisa C Heather

doi:10.1016/j.jacbts.2018.04.005

Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes

Michael Dodd, Maria da Luz Sousa Fialho, Claudia N. Montes Aparico, Matthew Kerr, Kerstin N. Timm, Julian L. Griffin, Joost J.F.P. Luiken, Jan F.C. Glatz, Damian J Tyler, Lisa C Heather

School of Life Sciences

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Abstract

• HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia.

• Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia.

• This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia.

• Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity.

• Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes.

Original language	English
Pages (from-to)	485-498
Number of pages	14
Journal	Journal of the American College of Cardiology: Basic to Translational Science
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.jacbts.2018.04.005
Publication status	Published - Aug 2018

Bibliographical note

NOTICE: this is the author’s version of a work that was accepted for publication in
Journal of the American College of Cardiology: Basic to Translational Science
Changes resulting from the publishing process, such as peer review, editing,
corrections, structural formatting, and other quality control mechanisms may not
be reflected in this document. Changes may have been made to this work since it
was submitted for publication. A definitive version was subsequently published in
Journal of the American College of Cardiology: Basic to Translational Science.
© 2018, Elsevier. Licensed under the Creative Commons AttributionNonCommercial-NoDerivatives
4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/

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10.1016/j.jacbts.2018.04.005Licence: CC BY

Dodd_et_al_Fatty_acids_JACCFinal published version, 2.31 MBLicence: CC BY

Mike Dodd
- Centre for Health and Life Sciences - Assistant Professor (Research)
Person: Teaching and Research

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Dodd, M., Sousa Fialho, M. D. L., Montes Aparico, C. N., Kerr, M., Timm, K. N., Griffin, J. L., Luiken, J. J. F. P., Glatz, J. F. C., Tyler, D. J., & Heather, L. C. (2018). Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes. Journal of the American College of Cardiology: Basic to Translational Science, 3(4), 485-498. https://doi.org/10.1016/j.jacbts.2018.04.005

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title = "Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes",

abstract = "• HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia.• Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia.• This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia.• Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity.• Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes.",

author = "Michael Dodd and {Sousa Fialho}, {Maria da Luz} and {Montes Aparico}, {Claudia N.} and Matthew Kerr and Timm, {Kerstin N.} and Griffin, {Julian L.} and Luiken, {Joost J.F.P.} and Glatz, {Jan F.C.} and Tyler, {Damian J} and Heather, {Lisa C}",

note = "NOTICE: this is the author{\textquoteright}s version of a work that was accepted for publication in Journal of the American College of Cardiology: Basic to Translational Science Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of the American College of Cardiology: Basic to Translational Science. {\textcopyright} 2018, Elsevier. Licensed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/",

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AU - Sousa Fialho, Maria da Luz

AU - Montes Aparico, Claudia N.

AU - Kerr, Matthew

AU - Timm, Kerstin N.

AU - Griffin, Julian L.

AU - Luiken, Joost J.F.P.

AU - Glatz, Jan F.C.

AU - Tyler, Damian J

AU - Heather, Lisa C

N1 - NOTICE: this is the author’s version of a work that was accepted for publication in Journal of the American College of Cardiology: Basic to Translational Science Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of the American College of Cardiology: Basic to Translational Science. © 2018, Elsevier. Licensed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

PY - 2018/8

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N2 - • HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia.• Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia.• This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia.• Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity.• Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes.

AB - • HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia.• Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia.• This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia.• Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity.• Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes.

U2 - 10.1016/j.jacbts.2018.04.005

DO - 10.1016/j.jacbts.2018.04.005

M3 - Article

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JO - JACC: Basic to Translational Science

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IS - 4

ER -

Fatty acids prevent Hypoxia-Inducible Factor 1α signalling in type 2 diabetes

Abstract

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