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Abstract
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.
Highlights
Obstructive sleep apnea (OSA) is a common disorder that affects 4–24% of men and 2–9% of women in the United States (Young et al, 1993), but the prevalence of OSA exceeds 30–50% in obese individuals Punjabi et al (2002), Vgontzas et al (2000), Young et al (1993), Tufik et al (2010), Young et al (2002)
Experiments in a mouse model of intermittent hypoxia (IH) mimicking oxyhemoglobin desaturations in patients with OSA showed that IH induces insulin resistance, glucose intolerance, and dyslipidemia in the absence of obesity (Li et al, 2005b, 2006, 2007; Iiyori et al, 2007; Savransky et al, 2007b), but the effects of IH are severe in the presence of obesity (Polotsky et al, 2003; Drager et al, 2011)
Applicability of findings in the Von Hippel-Lindau (VHL) KO model to hepatic steatosis induced by IH is uncertain. It remains unknown whether up-regulation of lipogenic genes during IH occurs due to direct activation of HIFs in the liver or predominantly due to the free fatty acids (FFA) flux from adipose tissue
Summary
Obstructive sleep apnea (OSA) is a common disorder that affects 4–24% of men and 2–9% of women in the United States (Young et al, 1993), but the prevalence of OSA exceeds 30–50% in obese individuals Punjabi et al (2002), Vgontzas et al (2000), Young et al (1993), Tufik et al (2010), Young et al (2002). OSA is associated with all manifestations of the metabolic syndrome, including visceral obesity, hypertension, dyslipidemia, and insulin resistance (Levy et al, 2009; Drager et al, 2010b; Sharma et al, 2011; Bonsignore et al, 2012). Recent clinical data suggests that metabolic dysfunction of OSA is associated with nocturnal IH, independent of obesity (Drager et al, 2010b; Bonsignore et al, 2012). Animal and human data indicate that IH of OSA may contribute to the progression of NAFLD, a common condition with the prevalence between 17 and 33% and the major risk factors being obesity and insulin resistance (Hilden et al, 1977; Nomura et al, 1988; Bellentani et al, 2000; Browning and Horton, 2004; Browning et al, 2004; Clark, 2006; McCullough, 2006). We will review available clinical evidence on the relationships between OSA and liver disease and examine putative www.frontiersin.org
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