Abstract
ABSTRACTPeroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases 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 PPARα 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 PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα 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 PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα 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 PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF.
Highlights
Acute liver failure (ALF) is a clinical syndrome defined by the sudden onset of severe liver injury and is characterized by encephalopathy and coagulopathy in individuals with previously normal liver function (Khan et al, 2006)
Peroxisome proliferator-activated receptor α (PPARα) activation decreases hepatocyte apoptosis, protecting against ALF We first evaluated whether PPARα activation could rescue liver injury by applying Wy-14643, a PPARα ligand activator
These results suggest that PPARα activation significantly reduces apoptotic cells and thereby protects mice from ALF induced by D-GalN/LPS
Summary
Acute liver failure (ALF) is a clinical syndrome defined by the sudden onset of severe liver injury and is characterized by encephalopathy and coagulopathy in individuals with previously normal liver function (Khan et al, 2006). Studies have demonstrated that PPARα plays a different role in cancer cells than in normal cells. PPARα activation is commonly implicated in hepatocarcinogenesis protocols for rodents in which its antiapoptotic action is assumed to play a crucial role (Misra et al, 2013; Misra and Reddy, 2014); activation of PPARα by exogenous agonists reduces tumor cell growth in cell lines derived from colorectal cancer (Grau et al, 2006). In a third normal cell system, PPARα agonist treatment has been shown to increase trefoil factor family-3 expression and attenuate apoptosis in the liver tissue of bile duct-ligated rats (Karakan et al, 2013). Our recent study has shown that PPARα activation protects the liver from acute injury by promoting the autophagy pathway in the D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF mouse model (Jiao et al, 2014). Whether PPARα plays a protective role in the liver by inhibiting hepatocyte apoptosis is yet to be determined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
