Chronic intermittent hypoxia promotes early intrahepatic endothelial impairment in rats with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a progressive disease that ranges from simple steatosis to cirrhosis. Obstructive sleep apnea syndrome (OSAS) and chronic intermittent hypoxia (CIH) are implicated in the pathogenesis of NAFLD. However, the overlapping consequences of CIH on liver sinusoidal endothelial function over time in NAFLD are largely unknown. We explored endothelial dysfunction in a rat model of NAFLD with a high-fat diet exposed to CIH [12 h/day, every 30 s to fractional concentration of oxygen ([Formula: see text] 8%-10%]. The livers were isolated and perfused, and the endothelial function was determined by testing the vasodilation of the liver circulation to increased concentrations of acetylcholine and von Willebrand factor (vWF) and intercellular adhesion molecule 1 (ICAM-1) expression. Phosphorylated endothelial nitric oxide synthase (p-eNOS), cGMP, and oxidative stress were assessed to determine nitric oxide bioavailability. Inflammation and fibrosis were evaluated by transaminases, myeloperoxidase activity, hydroxyproline, and histological evaluation. Hypoxia-inducible factors (HIFs) were studied as a marker of hypoxia and after a second insult with acetaminophen. CIH exposure provoked typical systemic features of OSAS and provoked a decreased response in vasodilation to acetylcholine. This was associated with increased oxidative stress and reduced p-eNOS and cGMP. The microcirculation impairment due to CIH preceded significant hepatic inflammation and fibrotic changes, despite the presence of HIF expression. In conclusion, CIH exacerbates endothelial dysfunction in NAFLD rats associated with increased oxidative stress and reduced nitric oxide bioavailability. This occurs before inflammation and fibrosis establish. Our results suggest that with CIH endothelial dysfunction should be considered an early target. We believe the findings are of relevance because we demonstrate that chronic intermittent hypoxia further augments impaired hepatic endothelial dysfunction in nonalcoholic fatty liver disease rats. Because obstructive sleep apnea syndrome is associated with systemic endothelial dysfunction in cardiovascular disorders, and chronic intermittent hypoxia is an independent and reversible risk factor for hypertension and coronary artery disease, we hypothesized that this entity may be of potential relevance in the pathophysiology of nonalcoholic fatty liver disease.