Peroxisome proliferator-activated receptor a activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway

Peroxisome proliferator-activated receptor alpha (PPAR alpha) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPAR alpha activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPAR alpha expression during ALF and the impact of PPAR alpha activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPAR alpha was significantly downregulated in the injured liver. PPAR alpha activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPAR alpha activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPAR alpha activation suppressed proinflammatory responses and inhibited phosphorylated NF-kappa Bp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPAR alpha activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPAR alpha activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPAR alpha-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.