Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver

Abstract

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

“…Our previous experiments in the mouse model showed that CIH increases lipid peroxidation and activates a redox-dependent transcription factor, NF-kB, in the liver (44,45). We have also shown that, in mice with diet-induced hepatic steatosis, but not in mice with normal livers, CIH increases liver levels of proinflammatory cytokines IL-1b, IL-6, macrophage inflammatory protein-2, and tumor necrosis factor-a as well as a1(I) collagen and indices of lobular inflammation and fibrosis (27,45,46). Our present report and previous experimental data suggest that the hypoxic stress of OSA may induce oxidative stress in the livers of patients with severe obesity, leading to inflammation and fibrosis, which culminate in NASH.…”

“…The ''second hit'' induces progression of hepatic steatosis to NASH (21). Obesity, age over 45 years, diabetes, hypertriglyceridemia, and hypertension have been identified as risk factors for the progression of NAFLD (24), but causes for NAFLD progression, which occurs in approximately 25-30% of patients with hepatic steatosis, remain unknown (25).We have previously used a mouse model of CIH and have shown that CIH induces insulin resistance in genetically obese mice and converts diet-induced hepatic steatosis to NASH (26,27). Although obesity and OSA have been implicated in the development of systemic inflammation, insulin resistance, and NAFLD (2-4, 10-21, 24, 28), the inflammatory, metabolic, and hepatic profiles of severe obesity with and without concomitant sleep apnea have not been elucidated.…”

“…We have previously used a mouse model of CIH and have shown that CIH induces insulin resistance in genetically obese mice and converts diet-induced hepatic steatosis to NASH (26,27). Although obesity and OSA have been implicated in the development of systemic inflammation, insulin resistance, and NAFLD (2-4, 10-21, 24, 28), the inflammatory, metabolic, and hepatic profiles of severe obesity with and without concomitant sleep apnea have not been elucidated.…”

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

“…Very little is known about this interaction [49,50]. Hypoxia induces oxidative stress in the brain [51,52] and is associated with increased levels of proinflammatory cytokines, such as TNF-α in pig [53], in humans [54] and in mice [55]. Indeed, the levels of TNF-α may remain elevated in the affected brain tissue for at least 24 h after an ischemic insult [16,56] and TNF-α itself causes oxidative stress in the brain [57].…”

Nonalcoholic fatty liver disease: a challenge for pediatricians

“…67 Still in the absence of obesity, chronic intermittent hypoxia leads to mild elevated levels of liver enzymes, 68 liver injury by oxidative stress and excessive glycogen accumulation in hepatocytes and sensitizes the liver for a second injury. 69 It seems that sleep apnea is the leading cause of adverse metabolic outcomes. Although, further research need to conclude whether a cause and effect relationship exist.…”