Chronic Intermittent Hypoxia-Induced Dysmetabolism Is Associated with Hepatic Oxidative Stress, Mitochondrial Dysfunction and Inflammation
Joana L. Fernandes,
Fátima O. Martins,
Elena Olea,
Jesus Prieto-Lloret,
Patrícia C. Braga,
Joana F. Sacramento,
Catarina O. Sequeira,
Ana P. Negrinho,
Sofia A. Pereira,
Marco G. Alves,
Asunción Rocher,
Silvia V. Conde
Affiliations
Joana L. Fernandes
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Fátima O. Martins
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Elena Olea
Departamento de Enfermeria, Universidad de Valladolid, 47005 Valladolid, Spain
Jesus Prieto-Lloret
Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47005 Valladolid, Spain
Patrícia C. Braga
Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
Joana F. Sacramento
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Catarina O. Sequeira
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Ana P. Negrinho
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Sofia A. Pereira
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
Marco G. Alves
Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
Asunción Rocher
Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47005 Valladolid, Spain
Silvia V. Conde
iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-069 Lisboa, Portugal
The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O2) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.
