Bistability in fatty-acid oxidation resulting from substrate inhibition.

In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct...

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Autores principales:	Fentaw Abegaz, Anne-Claire M F Martines, Marcel A Vieira-Lara, Melany Rios-Morales, Dirk-Jan Reijngoud, Ernst C Wit, Barbara M Bakker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/febc2d2c3e1e4399b08b47a1554814cc
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id	oai:doaj.org-article:febc2d2c3e1e4399b08b47a1554814cc
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spelling	oai:doaj.org-article:febc2d2c3e1e4399b08b47a1554814cc2021-12-02T19:58:06ZBistability in fatty-acid oxidation resulting from substrate inhibition.1553-734X1553-735810.1371/journal.pcbi.1009259https://doaj.org/article/febc2d2c3e1e4399b08b47a1554814cc2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009259https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct stable and one unstable steady state could be attained with different fluxes. The two stable states were referred to as low-flux (disease) and high-flux (healthy) state. By a modular kinetic approach we traced the origin and causes of the bistability back to the distributive kinetics and the conservation of CoA, in particular in the last rounds of the β-oxidation. We then extended the model to investigate various interventions that may confer health benefits by activating the pathway, including (i) activation of the last enzyme MCKAT via its endogenous regulator p46-SHC protein, (ii) addition of a thioesterase (an acyl-CoA hydrolysing enzyme) as a safety valve, and (iii) concomitant activation of a number of upstream and downstream enzymes by short-chain fatty-acids (SCFA), metabolites that are produced from nutritional fibers in the gut. A high concentration of SCFAs, thioesterase activity, and inhibition of the p46Shc protein led to a disappearance of the bistability, leaving only the high-flux state. A better understanding of the switch behavior of the mitochondrial fatty-acid oxidation process between a low- and a high-flux state may lead to dietary and pharmacological intervention in the treatment or prevention of obesity and or non-alcoholic fatty-liver disease.Fentaw AbegazAnne-Claire M F MartinesMarcel A Vieira-LaraMelany Rios-MoralesDirk-Jan ReijngoudErnst C WitBarbara M BakkerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009259 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Fentaw Abegaz Anne-Claire M F Martines Marcel A Vieira-Lara Melany Rios-Morales Dirk-Jan Reijngoud Ernst C Wit Barbara M Bakker Bistability in fatty-acid oxidation resulting from substrate inhibition.
description	In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct stable and one unstable steady state could be attained with different fluxes. The two stable states were referred to as low-flux (disease) and high-flux (healthy) state. By a modular kinetic approach we traced the origin and causes of the bistability back to the distributive kinetics and the conservation of CoA, in particular in the last rounds of the β-oxidation. We then extended the model to investigate various interventions that may confer health benefits by activating the pathway, including (i) activation of the last enzyme MCKAT via its endogenous regulator p46-SHC protein, (ii) addition of a thioesterase (an acyl-CoA hydrolysing enzyme) as a safety valve, and (iii) concomitant activation of a number of upstream and downstream enzymes by short-chain fatty-acids (SCFA), metabolites that are produced from nutritional fibers in the gut. A high concentration of SCFAs, thioesterase activity, and inhibition of the p46Shc protein led to a disappearance of the bistability, leaving only the high-flux state. A better understanding of the switch behavior of the mitochondrial fatty-acid oxidation process between a low- and a high-flux state may lead to dietary and pharmacological intervention in the treatment or prevention of obesity and or non-alcoholic fatty-liver disease.
format	article
author	Fentaw Abegaz Anne-Claire M F Martines Marcel A Vieira-Lara Melany Rios-Morales Dirk-Jan Reijngoud Ernst C Wit Barbara M Bakker
author_facet	Fentaw Abegaz Anne-Claire M F Martines Marcel A Vieira-Lara Melany Rios-Morales Dirk-Jan Reijngoud Ernst C Wit Barbara M Bakker
author_sort	Fentaw Abegaz
title	Bistability in fatty-acid oxidation resulting from substrate inhibition.
title_short	Bistability in fatty-acid oxidation resulting from substrate inhibition.
title_full	Bistability in fatty-acid oxidation resulting from substrate inhibition.
title_fullStr	Bistability in fatty-acid oxidation resulting from substrate inhibition.
title_full_unstemmed	Bistability in fatty-acid oxidation resulting from substrate inhibition.
title_sort	bistability in fatty-acid oxidation resulting from substrate inhibition.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/febc2d2c3e1e4399b08b47a1554814cc
work_keys_str_mv	AT fentawabegaz bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT anneclairemfmartines bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT marcelavieiralara bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT melanyriosmorales bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT dirkjanreijngoud bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT ernstcwit bistabilityinfattyacidoxidationresultingfromsubstrateinhibition AT barbarambakker bistabilityinfattyacidoxidationresultingfromsubstrateinhibition
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Bistability in fatty-acid oxidation resulting from substrate inhibition.

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