Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a key regulator to ameliorate liver injury incases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPAR alpha activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPAR alpha, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPAR alpha activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPAR alpha activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPAR alpha activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPAR alpha expression, as 4-PBA pre-treatment promoted upregulation of PPAR alpha, and inhibition of PPAR alpha by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPAR alpha activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPAR alpha inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPAR alpha activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPAR alpha could be a potential therapeutic strategy to ameliorate ALF.