Published in:
01-09-2017 | Original Research Paper
Peroxisome proliferator-activated receptor alpha mediates C/EBP homologous protein to protect mice from acute liver failure
Published in: Inflammation Research | Issue 9/2017
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Objective
Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to ameliorate liver injury in cases of acute liver failure (ALF). However, its intrinsic protective molecular mechanisms remain largely undetermined. C/EBP homologous protein (CHOP) is an important mediator of lipopolysaccharide (LPS)-induced inflammation. The aim of the present study was to test the hypothesis that PPARα activation alleviates liver inflammation to protect mice from acute liver failure (ALF) mediated by CHOP.
Methods
In a murine model induced by d-galactosamine (d-GalN, 700 mg/kg) and LPS (10 μg/kg), Wy-14643 (6 mg/kg) was administered to activate PPARα. The mice of different groups were killed 6 h after d-GalN/LPS injection, and the liver and blood were collected for analysis. To find out whether PPARα activation protects the liver from injury due to inflammation by regulating CHOP, we used expression plasmid to increase CHOP expression and demonstrated how PPARα mediated CHOP to regulate inflammation in vivo and in vitro.
Results
The expression of PPARα was downregulated and the expression of CHOP was upregulated with the development of d-GalN/LPS-induced liver injury. The protective molecular mechanisms of PPARα activation were dependent on the expression of CHOP. Indeed, (1) PPARα activation decreased the expression of CHOP; on the other hand, PPARα knockdown increased the expression of CHOP in vivo; (2) the depressed liver inflammation by PPARα activation was due to the downregulation of CHOP expression, because overexpression of CHOP by transfect plasmid reversed liver protection and increased liver inflammation again; (3) in vitro, PPARα inhibition by siRNA treatment increased the expression of proinflammatory cytokines, and CHOP siRNA co-transfection reversed the expression of proinflammatory cytokines.
Conclusions
Here, we demonstrated that PPARα activation contributes to liver protection and decreases liver inflammation in ALF, particularly through regulating CHOP. Our findings may provide a rationale for targeting PPARα as a potential therapeutic strategy to ameliorate ALF.