Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity

Oxidative stress has a critical role in the pathogenesis of acetaminophen (APAP) induced hepatocellular necrosis, and the identification of novel approaches to attenuate oxidative stress is essential to prevent/revert the disease. This study investigated the role of both HIF-1 and HIF-2 in the pathogenesis of APAP-induced oxidative stress, as well as the underlying mechanisms. In the present study, we initially found that knockout of HIF-1 alpha or HIF-2 alpha reduced APAP toxicity, and double knockout afforded the best protection. APAP treatment led to stabilization of both HIF-1 alpha and HIF-2 alpha in mouse livers. Moreover, the protective effects of HIF deficiency were related to the attenuated oxidative stress. Further experiments proved that PPAR alpha, a master regulator in cellular metabolism accounted for the HIF deficiency-caused protective impact on APAP toxicity. Inactivation of HIFs promoted the expression of peroxisome proliferator-activated receptor a (PPARa) in the liver, which in turn activated nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of PPARa or Nrf2 negated the hepatoprotection afforded by HIF deficiency. At last, examination of the PPARa promoter identified a HIF-binding site and HIF-dependent repression of PPARa in hepatocytes by luciferase reporter and EMSA study. Taken together, Our results demonstrate that HIFs are key suppressors of PPARa in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress when confronted with APAP. These findings are important to the etiology and therapeutics of APAP hepatotoxicity. The functional link between HIFs and PPARa may have more implications in liver physiology and other pathologic conditions than APAP injury.