Obstructive sleep apnea (OSA) is characterized by chronic intermittent
hypoxia (CIH). OSA is associated with
nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of
obesity. Lean C57BL/6J mice (n = 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n = 15). CIH caused liver injury with an increase in serum ALT (224 +/- 39 U/l versus 118 +/- 22 U/l in the IA group, P < 0.05), whereas AST and
alkaline phosphatase were unchanged. CIH also induced
hyperglycemia, a decrease in fasting serum
insulin levels, and mild elevation of fasting serum total
cholesterol and
triglycerides (TG). Liver TG content was unchanged, whereas
cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of
glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a
malondialdehyde (MDA)/
free fatty acids (FFA) ratio of 0.54 +/- 0.07 mmol/mol versus 0.30 +/- 0.01 mmol/mol in control animals (P < 0.01), and increased levels of active
nuclear factor kappaB (
NF-kappaB) in the nuclear fraction of hepatocytes, suggesting that CIH induced oxidative stress in the liver. Finally, CIH greatly exacerbated
acetaminophen-induced liver toxicity, causing fulminant hepatocellular injury.
CONCLUSION: In the absence of
obesity, CIH leads to mild liver injury via oxidative stress and excessive
glycogen accumulation in hepatocytes and sensitizes the liver to a second insult, whereas NASH does not develop.