Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study...

Descripción completa

Detalles Bibliográficos
Autores: Hernández-García, Miguel Á., Aldave-Orzaiz, Beatriz, Fernández-García, Carlos Ernesto, Fuertes-Yebra, Esther, Rey, Esther, Berlana, Ángela, Farré, Ramón, García-Monzón, Carmelo, Almendros, Isaac, Landete, Pedro, González-Rodríguez, Águeda
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/419639
Acceso en línea:http://hdl.handle.net/10261/419639
Access Level:acceso abierto
Palabra clave:Obstructive sleep apnea
CPAP
MASLD
Liver steatosis
Intermittent hypoxia
Steatosis
Lipid metabolism
id ES_f7a44093d82f8b732524661861c052d6
oai_identifier_str oai:digital.csic.es:10261/419639
network_acronym_str ES
network_name_str España
repository_id_str
spelling Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep ApneaHernández-García, Miguel Á.Aldave-Orzaiz, BeatrizFernández-García, Carlos ErnestoFuertes-Yebra, EstherRey, EstherBerlana, ÁngelaFarré, RamónGarcía-Monzón, CarmeloAlmendros, IsaacLandete, PedroGonzález-Rodríguez, ÁguedaObstructive sleep apneaCPAPMASLDLiver steatosisIntermittent hypoxiaSteatosisLipid metabolismObstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study aims to investigate the impact of oxygen normalization on metabolic dysfunction in OSA patients using continuous positive airway pressure (CPAP) therapy, and in mice exposed to IH followed by a reoxygenation period. In the clinical study, 76 participants (44 OSA patients and 32 controls) were analyzed. OSA patients had higher insulin resistance, triglycerides, very low density lipoprotein (VLDL) content, and liver enzyme levels, along with a higher prevalence of liver steatosis. After 18 months of CPAP therapy, OSA patients showed significant improvements in insulin resistance, lipid profiles (total cholesterol and VLDL), liver function markers (AST and albumin), and steatosis risk scores (Fatty Liver Index and OWLiver test). In the experimental study, IH induced hepatic lipid accumulation, oxidative stress, and inflammation, and reoxygenation reversed these deleterious effects in mice. At the molecular level, IH downregulated fatty acid oxidation (FAO)-related genes, thus impairing the FAO process. Reoxygenation maintained elevated levels of lipogenic genes but restored FAO gene expression and activity, suggesting enhanced lipid clearance despite ongoing lipogenesis. Indeed, serum β hydroxybutyrate, a key marker of hepatic FAO in patients, was impaired in OSA patients but normalized after CPAP therapy, supporting improved FAO function. CPAP therapy improves lipid profiles, liver function, and MASLD progression in OSA patients. Experimental findings highlight the therapeutic potential of oxygen normalization in reversing IH-induced liver damage by FAO pathway restoration, indicating a metabolic reprogramming in the liver.This work was supported by CIBERDEM (Instituto de Salud Carlos III, ISCIII, Spain) to AGR, grant PID2022-140774OB-I00 has been funded by MICIU/AEI/10.13039/501100011033 and by FEDER, UE to IA, and grant PI20/00837 from ISCIII/FEDER (Spain) to PL. SCI and MAR are supported by a predoctoral contract (FI20/00296 and FI23/00135, respectively) from ISCIII/FEDER (Spain).Peer reviewedMultidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/419639reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-140774OB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/antiox14080971https://doi.org/10.3390/antiox14080971Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4196392026-05-22T06:33:51Z
dc.title.none.fl_str_mv Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
title Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
spellingShingle Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
Hernández-García, Miguel Á.
Obstructive sleep apnea
CPAP
MASLD
Liver steatosis
Intermittent hypoxia
Steatosis
Lipid metabolism
title_short Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
title_full Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
title_fullStr Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
title_full_unstemmed Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
title_sort Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
dc.creator.none.fl_str_mv Hernández-García, Miguel Á.
Aldave-Orzaiz, Beatriz
Fernández-García, Carlos Ernesto
Fuertes-Yebra, Esther
Rey, Esther
Berlana, Ángela
Farré, Ramón
García-Monzón, Carmelo
Almendros, Isaac
Landete, Pedro
González-Rodríguez, Águeda
author Hernández-García, Miguel Á.
author_facet Hernández-García, Miguel Á.
Aldave-Orzaiz, Beatriz
Fernández-García, Carlos Ernesto
Fuertes-Yebra, Esther
Rey, Esther
Berlana, Ángela
Farré, Ramón
García-Monzón, Carmelo
Almendros, Isaac
Landete, Pedro
González-Rodríguez, Águeda
author_role author
author2 Aldave-Orzaiz, Beatriz
Fernández-García, Carlos Ernesto
Fuertes-Yebra, Esther
Rey, Esther
Berlana, Ángela
Farré, Ramón
García-Monzón, Carmelo
Almendros, Isaac
Landete, Pedro
González-Rodríguez, Águeda
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Obstructive sleep apnea
CPAP
MASLD
Liver steatosis
Intermittent hypoxia
Steatosis
Lipid metabolism
topic Obstructive sleep apnea
CPAP
MASLD
Liver steatosis
Intermittent hypoxia
Steatosis
Lipid metabolism
description Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study aims to investigate the impact of oxygen normalization on metabolic dysfunction in OSA patients using continuous positive airway pressure (CPAP) therapy, and in mice exposed to IH followed by a reoxygenation period. In the clinical study, 76 participants (44 OSA patients and 32 controls) were analyzed. OSA patients had higher insulin resistance, triglycerides, very low density lipoprotein (VLDL) content, and liver enzyme levels, along with a higher prevalence of liver steatosis. After 18 months of CPAP therapy, OSA patients showed significant improvements in insulin resistance, lipid profiles (total cholesterol and VLDL), liver function markers (AST and albumin), and steatosis risk scores (Fatty Liver Index and OWLiver test). In the experimental study, IH induced hepatic lipid accumulation, oxidative stress, and inflammation, and reoxygenation reversed these deleterious effects in mice. At the molecular level, IH downregulated fatty acid oxidation (FAO)-related genes, thus impairing the FAO process. Reoxygenation maintained elevated levels of lipogenic genes but restored FAO gene expression and activity, suggesting enhanced lipid clearance despite ongoing lipogenesis. Indeed, serum β hydroxybutyrate, a key marker of hepatic FAO in patients, was impaired in OSA patients but normalized after CPAP therapy, supporting improved FAO function. CPAP therapy improves lipid profiles, liver function, and MASLD progression in OSA patients. Experimental findings highlight the therapeutic potential of oxygen normalization in reversing IH-induced liver damage by FAO pathway restoration, indicating a metabolic reprogramming in the liver.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/419639
url http://hdl.handle.net/10261/419639
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-140774OB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/antiox14080971
https://doi.org/10.3390/antiox14080971
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424901749735424
score 15,811543

Similares en LA Referencia