Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation

Activated hepatic stellate cells (aHSCs), the main perpetrators of liver fibrosis, are a promising therapeutic target in the treatment of chronic liver disease. During liver injury, HSCs transcend from a quiescent to a fibrotic phenotype, a process which involves major metabolic reprogramming with a...

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Autores: Benedicto, AM, Lucantoni, F, Fuster-Martínez, I, Diaz-Pozo, P, Dorcaratto, D, Muñoz-Forner, E, Victor, VM, Esplugues, JV, Blas-García, A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p18389
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/18389
Access Level:acceso abierto
Palabra clave:Liver fibrosis
Hepatic stellate cells
Therapeutic targets
Mitochondria
Rilpivirine
TGF-beta
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spelling Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activationBenedicto, AMLucantoni, FFuster-Martínez, IDiaz-Pozo, PDorcaratto, DMuñoz-Forner, EVictor, VMEsplugues, JVBlas-García, ALiver fibrosisHepatic stellate cellsTherapeutic targetsMitochondriaRilpivirineTGF-betaActivated hepatic stellate cells (aHSCs), the main perpetrators of liver fibrosis, are a promising therapeutic target in the treatment of chronic liver disease. During liver injury, HSCs transcend from a quiescent to a fibrotic phenotype, a process which involves major metabolic reprogramming with altered mitochondrial function. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective and specifically antifibrotic effect in several animal models of chronic liver injury, as well as in vitro. Herein, we use HSCs activated with the profibrogenic cytokine TGF-beta to explore whether mitochondrial function is implicated in this effect. The mitochondrial bioenergetic profile, morphology and dynamics of TGF-beta-treated cells (48 h) were altered and these effects were prevented by co-treatment with clinically relevant concentrations of RPV. A MitoStress Test (Seahorse Analyzer) revealed that TGF-beta increased both oxygen consumption rate (basal respiration, maximal respiration and spare respiratory capacity) and extracellular acidification rate (indicative of increased glycolysis). Cells exposed to TGF-beta also displayed diminished mitochondrial membrane potential and enhanced mitochondrial fission. All of these effects were rescued with RPV. RNA sequencing analysis of cells exposed to TGF-beta revealed the presence of 338 differentially expressed genes that encode mitochondrial proteins (mito-DEGs), of which 139 and 199 were significantly up- and down-regulated (adjusted p<0.05). This alteration in 15 (10.79 %) and 31 (22.03 %) of the up-regulated and 16 (8.04 %) and 49 (24.62 %) of the down-regulated mitoDEGs was prevented with co-exposure to RPV 4 mu M or 8 mu M, respectively. In conclusion, alterations in mitochondrial function are implicated in the antifibrogenic action of RPV, pointing to potential novel antifibrotic targets.ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/18389BIOMEDICINE & PHARMACOTHERAPYISSN: 07533322ISSNe: 19506007reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p183892026-06-07T16:35:31Z
dc.title.none.fl_str_mv Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
title Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
spellingShingle Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
Benedicto, AM
Liver fibrosis
Hepatic stellate cells
Therapeutic targets
Mitochondria
Rilpivirine
TGF-beta
title_short Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
title_full Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
title_fullStr Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
title_full_unstemmed Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
title_sort Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
dc.creator.none.fl_str_mv Benedicto, AM
Lucantoni, F
Fuster-Martínez, I
Diaz-Pozo, P
Dorcaratto, D
Muñoz-Forner, E
Victor, VM
Esplugues, JV
Blas-García, A
author Benedicto, AM
author_facet Benedicto, AM
Lucantoni, F
Fuster-Martínez, I
Diaz-Pozo, P
Dorcaratto, D
Muñoz-Forner, E
Victor, VM
Esplugues, JV
Blas-García, A
author_role author
author2 Lucantoni, F
Fuster-Martínez, I
Diaz-Pozo, P
Dorcaratto, D
Muñoz-Forner, E
Victor, VM
Esplugues, JV
Blas-García, A
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Liver fibrosis
Hepatic stellate cells
Therapeutic targets
Mitochondria
Rilpivirine
TGF-beta
topic Liver fibrosis
Hepatic stellate cells
Therapeutic targets
Mitochondria
Rilpivirine
TGF-beta
description Activated hepatic stellate cells (aHSCs), the main perpetrators of liver fibrosis, are a promising therapeutic target in the treatment of chronic liver disease. During liver injury, HSCs transcend from a quiescent to a fibrotic phenotype, a process which involves major metabolic reprogramming with altered mitochondrial function. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective and specifically antifibrotic effect in several animal models of chronic liver injury, as well as in vitro. Herein, we use HSCs activated with the profibrogenic cytokine TGF-beta to explore whether mitochondrial function is implicated in this effect. The mitochondrial bioenergetic profile, morphology and dynamics of TGF-beta-treated cells (48 h) were altered and these effects were prevented by co-treatment with clinically relevant concentrations of RPV. A MitoStress Test (Seahorse Analyzer) revealed that TGF-beta increased both oxygen consumption rate (basal respiration, maximal respiration and spare respiratory capacity) and extracellular acidification rate (indicative of increased glycolysis). Cells exposed to TGF-beta also displayed diminished mitochondrial membrane potential and enhanced mitochondrial fission. All of these effects were rescued with RPV. RNA sequencing analysis of cells exposed to TGF-beta revealed the presence of 338 differentially expressed genes that encode mitochondrial proteins (mito-DEGs), of which 139 and 199 were significantly up- and down-regulated (adjusted p<0.05). This alteration in 15 (10.79 %) and 31 (22.03 %) of the up-regulated and 16 (8.04 %) and 49 (24.62 %) of the down-regulated mitoDEGs was prevented with co-exposure to RPV 4 mu M or 8 mu M, respectively. In conclusion, alterations in mitochondrial function are implicated in the antifibrogenic action of RPV, pointing to potential novel antifibrotic targets.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/18389
url https://incliva.portalinvestigacion.com/publicaciones/18389
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
publisher.none.fl_str_mv ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
dc.source.none.fl_str_mv BIOMEDICINE & PHARMACOTHERAPY
ISSN: 07533322
ISSNe: 19506007
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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