Normalization of Oxygen Levels Induces a Metabolic Reprogramming in Livers Exposed to Intermittent Hypoxia Mimicking Obstructive Sleep Apnea
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Polygraphic Study
2.3. Inclusion and Exclusion Criteria
2.4. Clinical and Laboratory Assessment
2.5. Serum Metabolomic Analysis
2.6. Animal Care and Intermittent Hypoxia Protocol Followed by Reoxygenation
2.7. Histopathological Evaluation
2.8. Assessment of Lipid Accumulation
2.9. IBA1 (Ionized Calcium-Binding Adapter Molecule 1) Immunohistochemistry
2.10. 4-HNE (4-Hydroxynonenal) Immunohistochemistry
2.11. Analysis of ORO Staining and IHQ Images
2.12. Fatty Acid Oxidation (FAO) Assay
2.13. Quantitative Real-Time PCR (RT-qPCR)
2.14. β-Hydroxybutyrate Assay Kit Assay
2.15. Statistical Analysis
3. Results
3.1. Characteristics of the Study Population and Prevalence of Metabolic Disorders
3.2. Normalization of Oxygen Levels Reverses Lipid Accumulation in Livers from Mice Exposed to IH
3.3. IH Impairs Liver FAO in Mice, Triggering an Increase in Hepatic Oxidative Stress
3.4. Reoxygenation Induces a Metabolic Reprogramming and Reduces Oxidative Stress in Livers from Mice Exposed to IH
3.5. CPAP Treatment Normalizes Circulating Levels of β-Hydroxybutyrate, a Marker for Hepatic FAO, in OSA Patients
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Accession Number | Forward (5′ → 3′) | Reverse (5′ → 3′) |
---|---|---|---|
m-36b4 | NM_007475.5 | AGATGCAGCAGATCCGCAT | GTTCTTGCCATCAGCACC |
m-Srebf1 | NM_011480.4 | GGCCGAGATGTGCGAACT | AGCTGGAGCATGTCTTCGATG |
m-Fasn | NM_007988.3 | CCCTTGATGAAGAGGGATCA | ACTCCACAGGTGGGAACAAG |
m-Scd1 | NM_009127.4 | TTCTTGCGATACACTCTGGTGC | CGGGATTGAATGTTCTTGTCGT |
m-Ppara | NM_011144.6 | AGAGCCCCATCTGTCCTCTC | ACTGGTAGTCTGCAAAACCAAA |
m-Pparg | NM_001308354.2 | TCGCTGATGCACTGCCTATG | GAGAGGTCCACAGAGCTGATT |
m-Ppargc1a | NM_008904.3 | AAGTGTGGAACTCTCTGGAACTG | GGGTTATCTTGGTTGGCTTTATG |
m-Cpt1b | NM_009948.2 | CTCCATGGGACTGGTCGATT | CCAAAGTGGCCATACCTTTCC |
m-Cpt2 | NM_009949.3 | GAATGACAGCCAGTTCAGGAAGA | CCTTCCCAATGCCGTTCTC |
m-Acox2 | NM_053115.2 | TTGATGGAGGCATCCCAAA | CACGTTGGATGAGGCTTTCA |
m-Ehhadh | NM_023737.3 | CCCACTCCCTGGCTATGATC | CAGTTGGACTGATGGCATTGA |
m-Cyp4a10 | NM_010011.3 | CACTGGTTCTTTGGGCATGA | TCTCTATGCACGACACAATTTCCT |
Control (N = 32) | OSA (N = 44) | p-Value | |
---|---|---|---|
Age (years) | 54.38 ± 8.53 | 59.36 ± 9.04 | 0.0174 |
Male sex, n (%) | 12 (37.5) | 30 (68.2) | 0.0079 |
Body mass index (kg/m2) | 28.91 ± 5.54 | 30.23 ± 6.14 | 0.3374 |
AHI (h−1) | 2.12 ± 1.31 | 41.11 ± 19.71 | <0.0001 |
Glucose (mg/dL) | 97.38 ± 13.38 | 103.40 ± 16.09 | 0.0902 |
HbA1c (%) | 5.62 ± 0.53 | 5.71 ± 0.48 | 0.4435 |
HOMA-IR | 2.93 ± 2.28 | 4.76 ± 3.52 | 0.0120 |
Triglycerides (mg/dL) | 106.47 ± 66.57 | 129.80 ± 75.76 | 0.0399 |
Total cholesterol (mg/dL) | 196.81 ± 39.17 | 188.50 ± 38.21 | 0.3585 |
HDL (mg/dL) | 57.53 ± 12.96 | 53.93 ± 19.13 | 0.0617 |
LDL (mg/dL) | 115.22 ± 30.75 | 108.30 ± 35.51 | 0.3780 |
VLDL (mg/dL) | 21.25 ± 13.25 | 26.20 ± 15.04 | 0.0339 |
ALT (IU/L) | 18.78 ± 7.34 | 23.52 ± 9.85 | 0.0116 |
AST (IU/L) | 20.28 ± 5.61 | 22.00 ± 7.21 | 0.2650 |
GGT (IU/L) | 22.19 ± 13.03 | 30.20 ± 16.23 | 0.0240 |
LDH (IU/L) | 182.72 ± 36.12 | 182.20 ± 34.82 | 0.9478 |
ALP (IU/L) | 69.63 ± 22.69 | 68.05 ± 20.64 | 0.7530 |
Total bilirubin (IU/L) | 0.57 ± 0.48 | 0.57 ± 0.32 | 0.340 |
Albumin (g/dL) | 4.38 ± 0.27 | 4.41 ± 0.25 | 0.5677 |
Platelets (109/L) | 226.31 ± 71.27 | 234.10 ± 51.73 | 0.5828 |
Iron (µg/dL) | 78.47 ± 33.50 | 87.66 ± 33.22 | 0.2391 |
C-Reactive Protein (mg/L) | 0.42 ± 0.59 | 0.31 ± 0.24 | 0.9979 |
FLI | 46.33 ± 28.65 | 66.26 ± 29.25 | 0.0042 |
NAFLD FS | −1.43 ± 1.29 | −1.14 ± 1.03 | 0.2706 |
HFS | 0.06 ± 0.07 | 0.07 ± 0.10 | 0.4614 |
Features | OSA (N = 44) | p-Value | |
---|---|---|---|
Pre-CPAP (N = 44) | Post-CPAP (N = 44) | ||
Age (years) | 59.36 ± 9.04 | 61.20 ± 9.19 | <0.0001 |
Male sex, n (%) | 30 (68.2) | 30 (68.2) | 1.0000 |
Body mass index (kg/m2) | 30.23 ± 6.14 | 30.12 ± 5.25 | 0.7755 |
AHI (h−1) | 41.11 ± 19.71 | 7.12 ± 15.73 | <0.0001 |
Glucose (mg/dL) | 103.40 ± 16.09 | 105.30 ± 18.40 | 0.3246 |
HbA1c (%) | 5.71 ± 0.48 | 5.64 ± 0.47 | 0.1613 |
HOMA-IR | 4.76 ± 3.52 | 4.86 ± 4.08 | 0.7838 |
Triglycerides (mg/dL) | 129.80 ± 75.76 | 112.20 ± 56.74 | 0.0656 |
Total cholesterol (mg/dL) | 188.50 ± 38.21 | 175.30 ± 36.08 | 0.0044 |
HDL (mg/dL) | 53.93 ± 19.13 | 53.64 ± 13.16 | 0.0663 |
LDL (mg/dL) | 108.30 ± 35.51 | 97.66 ± 34.61 | 0.0799 |
VLDL (mg/dL) | 26.20 ± 15.04 | 22.45 ± 11.31 | 0.0304 |
ALT (IU/L) | 23.52 ± 9.85 | 23.11 ± 10.27 | 0.3311 |
AST (IU/L) | 22.00 ± 7.21 | 19.68 ± 6.35 | 0.0088 |
GGT (IU/L) | 30.20 ± 16.23 | 29.84 ± 16.86 | 0.6819 |
LDH (IU/L) | 182.20 ± 34.82 | 169.40 ± 34.55 | 0.0002 |
ALP (IU/L) | 68.05 ± 20.64 | 74.93 ± 24.97 | 0.0011 |
Total bilirubin (IU/L) | 0.57 ± 0.32 | 0.57 ± 0.29 | 0.8502 |
Albumin (g/dL) | 4.41 ± 0.25 | 4.61 ± 0.21 | <0.0001 |
Platelets (109/L) | 234.10 ± 51.73 | 230.30 ± 52.06 | 0.4296 |
Iron (µg/dL) | 87.66 ± 33.22 | 93.73 ± 29.10 | 0.2265 |
C-Reactive Protein (mg/L) | 0.31 ± 0.24 | 0.24 ± 0.19 | 0.0599 |
FLI | 66.26 ± 29.25 | 64.62 ± 28.14 | 0.3828 |
NAFLD FS | −1.14 ± 1.03 | −1.22 ± 1.20 | 0.4821 |
Hepamet FS | 0.07 ± 0.10 | 0.07 ± 0.09 | 0.7298 |
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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
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 StyleHernández-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 StyleHernández-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