35 The lack of an increase in steatosis compared to controls is p

35 The lack of an increase in steatosis compared to controls is perhaps not unexpected given

that control group mice were also treated with 6 months of high-fat-diet feeding. The model that is emerging from these studies suggests that milder periods of hypoxia, such as moderate OSA, are insufficient by themselves to cause progression to hepatitis/steatohepatitis. However, when CIH is added to a primary insult, such as diet-induced steatosis, there is a predilection toward progression of liver injury. Corroborating evidence from other disease models includes the observation that sublethal acetaminophen poisoning resulted in fulminant liver failure when given in combination with CIH.36 A recent study combined CIH with daily injections of low-dose acetaminophen (APAP, 200 mg/kg) in mice for 4 weeks. At the end of the study Selleck MK-1775 period, CIH/APAP mice had markedly elevated liver enzymes, including CFTR modulator serum AST, ALT, gamma-glutamyl transferase (GGT), and total bilirubin, whereas no elevation was observed in mice with APAP alone, and only AST increased in mice with CIH alone.36 Some evidence relates to the interaction between the HIF pathway and APAP toxicity. HIF1α nuclear protein was observed to accumulate within 1 hour after a toxic dose (300 mg/kg) of APAP; this increase in HIF1α was prevented by N-acetylcysteine.37 Pretreatment with

salidroside, an extract of an herbal compound used in Chinese medicine to ameliorate mountain sickness, was able to prevent ALT, AST, and serum tumor necrosis factor alpha (TNF-α) in a mouse model of sublethal APAP toxicity as well as a decrease in HIF1α immunostaining compared to untreated controls.38 It is unknown whether the role of HIF1α in APAP injury is protective or deleterious; for example, treatment of APAP-challenged mice with hyperbaric oxygen was able to improve survival, even though it increased HIF1 protein levels and the downstream target Glut1.39 Recent work showed that deletion of HIF1α was protective against APAP toxicity at 6 but

not 24 hours, suggesting that HIF1α may play more of a learn more role in early, rather than late APAP toxicity.40 In that study, a conditional knockout of HIF1α was generated through an inducible ubiquitin promoter, resulting in whole body deficiency of HIF1α. Mice were then exposed to APAP and mice with HIF deficiency appeared to have decreased liver damage at 6 hours, but not at 24 hours. The emerging picture suggests that HIF1α is a component of the cellular response to APAP injury, but that the complexity of this metabolic insult involves other factors as it develops over time. It is possible that further research will identify therapies that can modify hypoxia inducible factor activity and thereby alter the progression of APAP toxicity at particular points in the evolution of liver injury.

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