Effect of peroxisome proliferator activated receptor α on endoplasmic reticulum stress in acute liver failure mice

Abstract

Objective To study the role of peroxisome proliferator activated receptor α (PPARα) on serious endoplasmic reticulum stress in acute liver failure (ALF) mice induced by D-Galactosamine/lipopolysaccharide (D-GalN/LPS). Methods ALF model was established by intraperitoneal injection of D-GalN/LPS in C57BL/6 mice. Animal experimental groups included the control group (corresponding volume phosphate buffered saline, 10 mice), model group (16 mice), Wy-14643 group (6 mg/kg Wy-14643 by tail vein on 2 h before model establishment).Meanwhile, mice in the model group further divided into three subgroup according to 1, 3, 6 h after D-GaN/LPS injection. The expression of C/EBP homologous protein (CHOP) and peroxisome proliferator activated receptor α (PPARα) among subgroup and the control group were compared. The levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were detected, the expression of caspase-3, cleaved caspase-3 and CHOP were examined by Western-blotting on 6 h after model establishment. The other 13 mice were injected 100 mg/kg 4-phenylbutyrate (4-PBA) on 6 h before model establishment as the 4-PBA group. The PPARα protein and mRNA were detected and compared. Results In the model group on 3, 6 h after D-GaN/LPS injection, the expression of CHOP increased (F = 6.341, P = 0.025), and PPARα decreased (F = 7.115, P = 0.022) as compared with those in the control group during the progression of ALF. The ALT, AST, caspase-3, cleaved caspase-3 and CHOP among the control group, model group and Wy-14643 group all showed significant differences (F = 8.454, P = 0.027; F = 10.252, P = 0.016; F = 6.231, P = 0.042; F = 30.072, P < 0.001; F = 8.596, P = 0.014). And the levels of ALT [(524 ± 330) U/L vs.(1 465 ± 485) U/L] and AST [(1 227 ± 314) U/L vs.(4 038 ± 1 537) U/L] in the Wy-14643 group were much lower than those in the model group (all P < 0.05). In the control group and Wy-14643 group, the expression of caspase-3 increased markedly, cleaved caspase-3 and CHOP decreased obviously as compared with those in the model group (all P < 0.05). Meanwhile, the PPARα mRNA and protein in the 4-PBA group were much higher than those in the model group (F = 6.665, P = 0.017; F = 5.441, P = 0.043). Conclusion PPARα may have the protective effects of liver function in ALF mice by inhibiting serious endoplasmic reticulum stress. Key words: Peroxisome proliferator-activated receptor alpha; Liver failure, acute; Endoplasmic reticulum; Mice