4-phenylbutyric acid attenuates endoplasmic reticulum stress-mediated apoptosis and protects the hepatocytes from intermittent hypoxia-induced injury

Purpose To investigate the effect of 4-phenylbutyric acid (4-PBA) on intermittent hypoxia (IH)-induced liver cell injury and to clarify the underlying mechanisms. Methods L02 cells (normal human liver cells) were cultured in normoxic condition or subjected to intermittent hypoxia for 4, 8, and 12h. A part of hypoxia-treated L02 cells was applied with 4-PBA 1h before exposure to hypoxia. The effect of 4-PBA on liver injury, hepatocyte apoptosis, endoplasmic reticulum stress (ERS), and PERK-eIFa2-ATF4-CHOP apoptotic pathway was investigated. Results (1) IH caused apoptosis in hepatocyte; (2) IH caused ERS in hepatocyte; (3) IH caused hepatic injury; (4) 4-PBA attenuated IH-induced liver cell injury; (5) 4-PBA protected liver cell from IH-induced apoptosis; (6) 4-PBA suppressed ERS-related apoptotic pathway (PERK-eIFa2-ATF4-CHOP), but did not suppress IH-induced unfold protein reaction (UPR). Conclusions 4-PBA could protect liver cells by suppressing IH-induced apoptosis mediated by ERS, but not by reducing the UPR.