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Antioxidants
Volume 14
Issue 8
10.3390/antiox14080971
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

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

by
Miguel Á. Hernández-García
1,†,
Beatriz Aldave-Orzáiz
2,†,
Carlos Ernesto Fernández-García
1,
Esther Fuertes-Yebra
1,
Esther Rey
1,
Ángela Berlana
1,‡,
Ramón Farré
3,4,5,
Carmelo García-Monzón
1,
Isaac Almendros
3,4,5,
Pedro Landete
2,6 and
Águeda González-Rodríguez
6,7,*
1
Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, 28006 Madrid, Spain
2
Respiratory Medicine Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa Hospital Universitario de La Princesa, 28006 Madrid, Spain
3
Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain
5
Instituto d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain
6
Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid, 28029 Madrid, Spain
7
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors share senior authorship.
Antioxidants 2025, 14(8), 971; https://doi.org/10.3390/antiox14080971 (registering DOI)
Submission received: 31 May 2025 / Revised: 24 July 2025 / Accepted: 30 July 2025 / Published: 7 August 2025
(This article belongs to the Special Issue Oxidative Stress in Sleep Disorders)
Versions Notes

Abstract

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.
Keywords: obstructive sleep apnea; CPAP; MASLD; liver steatosis; intermittent hypoxia; steatosis; li-pid metabolism obstructive sleep apnea; CPAP; MASLD; liver steatosis; intermittent hypoxia; steatosis; li-pid metabolism

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MDPI and ACS Style

Hernández-García, M.Á.; Aldave-Orzáiz, B.; Fernández-García, C.E.; Fuertes-Yebra, E.; Rey, E.; Berlana, Á.; Farré, R.; García-Monzón, C.; Almendros, I.; Landete, P.; et al. Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea. Antioxidants 2025, 14, 971. https://doi.org/10.3390/antiox14080971

AMA Style

Hernández-García MÁ, Aldave-Orzáiz B, Fernández-García CE, Fuertes-Yebra E, Rey E, Berlana Á, Farré R, García-Monzón C, Almendros I, Landete P, et al. Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea. Antioxidants. 2025; 14(8):971. https://doi.org/10.3390/antiox14080971

Chicago/Turabian Style

Hernández-García, Miguel Á., Beatriz Aldave-Orzáiz, Carlos Ernesto Fernández-García, Esther Fuertes-Yebra, Esther Rey, Ángela Berlana, Ramón Farré, Carmelo García-Monzón, Isaac Almendros, Pedro Landete, and et al. 2025. "Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea" Antioxidants 14, no. 8: 971. https://doi.org/10.3390/antiox14080971

APA Style

Hernández-García, M. Á., Aldave-Orzáiz, B., Fernández-García, C. E., Fuertes-Yebra, E., Rey, E., Berlana, Á., Farré, R., García-Monzón, C., Almendros, I., Landete, P., & González-Rodríguez, Á. (2025). Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea. Antioxidants, 14(8), 971. https://doi.org/10.3390/antiox14080971

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