Background: Hypoxic condition induced by obstructive sleep apnea syndrome (OSAS) involves in the development of NAFLD. Previous studies indicated HIF-2α was correlated with lipid metabolism. However, the potential mechanisms of HIF-2α in the progress of NAFLD was unclear. Our study aimed to detect the molecular mechanisms.
Methods: We established steatosis LO2 cells model and mouse NAFLD model, then exposed to intermittent hypoxia (IH) treatment, We detected the lipid accumulation in liver and the expression of HIF-1α and HIF-2α. Furthermore, we treated steatosis hepatocytes with hypoxia, HIF-2α siRNA, PPARα agonists and inhibitors respectively. Meanwhile, we exposed mouse NAFLD mode to IH or IH with PPARα agonists.
Results: Steatosis hepatocytes exhibited more sensitive to hypoxia and more likely to occur lipid accumulation. Moreover, we found lipid accumulation in hepatocytes was ameliorated by HIF-2α silence or PPARα agonist. HIF-2α overexpression suppressed PPARα leading to PGC-1α, NRF-1, ESRRα downregulation and impaired mitochondrial function. We also found lipolysis genes such as CPT1α, CPT2α, ACOX1, ACOX2 were downregulated, and lipogenesis genes including LXRα, FAS, SCD1 were upregulated.
So we concluded HIF-2α induced by hypoxia exacerbates NAFLD progression by suppressing β-oxidation via PPARα.
J. Chen: None. J. Chen: None. H. Fu: None. Y. Li: None. S. Luo: None. L. Wang: None. H. Lu: None.
National Natural Science Foundation of China (81670815); Natural Science Foundation of Guangdong Province (2016A030313279); Sun Yat-sen University (17YKZD23)
