Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection

ABSTRACT Dengue virus (DENV) is among the most important human arboviruses and is clinically and experimentally associated with lipid metabolism disorders. Using high-resolution respirometry, we analyzed the metabolic switches induced by DENV in a human hepatic cell line. This experimental approach...

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Autores principales:	Lorena O. Fernandes-Siqueira, Julianna D. Zeidler, Bruna G. Sousa, Thiago Ferreira, Andrea T. Da Poian
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Crabtree effect dengue virus energy metabolism fatty acid oxidation high-resolution respirometry mitochondrial function Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/16ca765524a04f0494227813eaf83815
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spelling	oai:doaj.org-article:16ca765524a04f0494227813eaf838152021-11-15T15:22:01ZAnaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection10.1128/mSphere.00458-172379-5042https://doaj.org/article/16ca765524a04f0494227813eaf838152018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00458-17https://doaj.org/toc/2379-5042ABSTRACT Dengue virus (DENV) is among the most important human arboviruses and is clinically and experimentally associated with lipid metabolism disorders. Using high-resolution respirometry, we analyzed the metabolic switches induced by DENV in a human hepatic cell line. This experimental approach allowed us to determine the contribution of fatty acids, glutamine, glucose, and pyruvate to mitochondrial bioenergetics, shedding light on the mechanisms involved in DENV-induced metabolic alterations. We found that while infection strongly inhibits glutamine oxidation, it increases the cellular capacity of metabolizing glucose; remarkably, though, this substrate, instead being used as an energy source, performs an anaplerotic role in the oxidation of endogenous lipids. Fatty acids become the main energetic substrate in infected cell, and through the pharmacological modulation of β-oxidation we demonstrated that this pathway is essential for virus replication. Interestingly, infected cells were much less susceptible to the Crabtree effect, i.e., the glucose-mediated inhibition of mitochondrial oxygen consumption, suggesting that infection favors cellular respiration by increasing ADP availability. IMPORTANCE Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology.Lorena O. Fernandes-SiqueiraJulianna D. ZeidlerBruna G. SousaThiago FerreiraAndrea T. Da PoianAmerican Society for MicrobiologyarticleCrabtree effectdengue virusenergy metabolismfatty acid oxidationhigh-resolution respirometrymitochondrial functionMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Crabtree effect dengue virus energy metabolism fatty acid oxidation high-resolution respirometry mitochondrial function Microbiology QR1-502
spellingShingle	Crabtree effect dengue virus energy metabolism fatty acid oxidation high-resolution respirometry mitochondrial function Microbiology QR1-502 Lorena O. Fernandes-Siqueira Julianna D. Zeidler Bruna G. Sousa Thiago Ferreira Andrea T. Da Poian Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
description	ABSTRACT Dengue virus (DENV) is among the most important human arboviruses and is clinically and experimentally associated with lipid metabolism disorders. Using high-resolution respirometry, we analyzed the metabolic switches induced by DENV in a human hepatic cell line. This experimental approach allowed us to determine the contribution of fatty acids, glutamine, glucose, and pyruvate to mitochondrial bioenergetics, shedding light on the mechanisms involved in DENV-induced metabolic alterations. We found that while infection strongly inhibits glutamine oxidation, it increases the cellular capacity of metabolizing glucose; remarkably, though, this substrate, instead being used as an energy source, performs an anaplerotic role in the oxidation of endogenous lipids. Fatty acids become the main energetic substrate in infected cell, and through the pharmacological modulation of β-oxidation we demonstrated that this pathway is essential for virus replication. Interestingly, infected cells were much less susceptible to the Crabtree effect, i.e., the glucose-mediated inhibition of mitochondrial oxygen consumption, suggesting that infection favors cellular respiration by increasing ADP availability. IMPORTANCE Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology.
format	article
author	Lorena O. Fernandes-Siqueira Julianna D. Zeidler Bruna G. Sousa Thiago Ferreira Andrea T. Da Poian
author_facet	Lorena O. Fernandes-Siqueira Julianna D. Zeidler Bruna G. Sousa Thiago Ferreira Andrea T. Da Poian
author_sort	Lorena O. Fernandes-Siqueira
title	Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
title_short	Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
title_full	Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
title_fullStr	Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
title_full_unstemmed	Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection
title_sort	anaplerotic role of glucose in the oxidation of endogenous fatty acids during dengue virus infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/16ca765524a04f0494227813eaf83815
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Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection

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