Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Glucose Starvation or Pyruvate Dehydrogenase Activation Induce A Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation

Abrar Ul Haq Khan
,
Hamideh Salehi
ORCID logo ,
Catherine Alexia
,
José M. Valdivielso
ORCID logo ,
Milica Bozic Stanojevic
,
Isabel Cristina López-Mejía
,
Lluis Fajas
,
Sabine Gerbal-Chaloin
ORCID logo ,
Martine Daujat-Chavanieu
ORCID logo ,
Delphine Gitenay
ORCID logo ,
Martín Villalba
* ORCID logo
Version 1 : Received: 5 April 2022 / Approved: 8 April 2022 / Online: 8 April 2022 (11:04:49 CEST)

A peer-reviewed article of this Preprint also exists.

Khan, A.U.H.; Salehi, H.; Alexia, C.; Valdivielso, J.M.; Bozic, M.; Lopez-Mejia, I.C.; Fajas, L.; Gerbal-Chaloin, S.; Daujat-Chavanieu, M.; Gitenay, D.; Villalba, M. Glucose Starvation or Pyruvate Dehydrogenase Activation Induce a Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation. Cells 2022, 11, 1392. Khan, A.U.H.; Salehi, H.; Alexia, C.; Valdivielso, J.M.; Bozic, M.; Lopez-Mejia, I.C.; Fajas, L.; Gerbal-Chaloin, S.; Daujat-Chavanieu, M.; Gitenay, D.; Villalba, M. Glucose Starvation or Pyruvate Dehydrogenase Activation Induce a Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation. Cells 2022, 11, 1392.

Abstract

Cells have metabolic flexibility that allows them to adapt to changes in substrate availability. Two highly relevant metabolites are glucose and fatty acids (FA), and hence, glycolysis and fatty acid oxidation (FAO) are key metabolic pathways leading to energy production. Both pathways affect each other, and in the absence of one substrate, metabolic flexibility allows cells to maintain sufficient energy production. Here we show that glucose starvation or sustained pyruvate dehy-drogenase (PDH) activation by dichloroacetate (DCA) induce a large genetic remodeling to pro-pel FAO. The extracellular signal-regulated kinase 5 (ERK5) is a key effector of this multistep metabolic remodeling. First, there is an increase in the lipid transport by expression of low-density lipoprotein receptor-related proteins (LRP), e.g. CD36, LRP1 and others. Second, an increase of the expression of members of the acyl-CoA synthetase long-chain (ACSL) family acti-vates FA. Finally, the expression of the enzymes that catalyze the initial step in each cycle of FAO, i.e. the acyl-CoA dehydrogenases (ACADs), is induced. All of these pathways lead to enhanced cellular FAO. In summary, we show here that different families of enzymes, which are essential to perform FAO, are regulated by the signaling pathway, i.e. MEK5/ERK5, which transduces changes from the environment to genetic adaptations.

Keywords

fatty acid oxidation; glycolysis; ERK5; metabolic flexibility; metabolic plasticity

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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