Chronic intermittent hypoxia predisposes to liver injury†

Abstract

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 ( O bstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH). 1 OSA is a common disease, present in 2% of women and 4% of men in the general U.S. population; however, the prevalence rises to 40% to 60% in obese individuals. 2,3 CIH of OSA has been associated with an increased risk of hypertension, type 2 diabetes, dyslipidemia, and atherosclerosis, independent of underlying obesity. 2,4-9 Moreover, studies in rodent models of intermittent hypoxia (IH) demonstrated that CIH can cause hypertension, 10 insulin resistance, 11 and dyslipidemia. 12,13 Thus, CIH of OSA has been implicated in causality of cardiovascular and metabolic disorders, independent of obesity.An emerging body of evidence indicates that OSA is associated with non-alcoholic steatohepatitis (NASH) and chronic liver injury in obese individuals. 14,15 Whether OSA can confer risk of NASH, independent of obesity, remains unclear. Two major mechanisms have been implicated in NASH: (1) hepatic steatosis, which is linked to insulin resistance; and (2) increased levels of oxidative stress with liver injury and subsequent inflammation. 16,17 We previously showed that CIH leads to progression of hepatic steatosis and insulin resistance in leptin-deficient obese mice. 12 However, the effects of CIH on hepatic lipids in the absence of obesity have not been examined. Whereas OSA and CIH induce oxidative stress and inflammation in multiple organs and tissues, 18-21 the impact

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

“…We hypothesize that severe obesity per se acts as ''the first hit'' in the progression of NAFLD inducing hepatic steatosis, whereas the presence of CIH of OSA acts as the ''second hit'' (21), inducing progression of hepatic steatosis to NASH. 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 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.…”

Effects of dietary guanidinoacetic acid and betaine supplementation on performance, blood biochemical parameters and antioxidant status of broilers subjected to cold stress

“…In hypoxia, serum cholesterol and LDL levels in mice fed creatine supplementation were lower compared to the control birds fed normal diet (Savransky et al 2007). High basal cholesterol levels and reduced blood total cholesterol have been observed in human males and females fed supplemental creatine (Earnest et al 1996).…”

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

“…Several studies have considered the mechanism of facilitated glycogen accumulation of OCCC (12,13), but a conclusion has not yet been reached. Some studies have found that the glycogen accumulation in several kinds of tumor cells was accelerated under hypoxic conditions (14)(15)(16)(17)(18). Under such a hypoxic environment, hypoxia-inducible factor 1 (HIF1) is expressed and functions as the main factor regulating the metabolism of the cell (19).…”