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

Peroxisome proliferator-activated receptor α (PPAR α ) 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 α activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPAR α expression during ALF and the impact of PPAR α 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 α was significantly downregulated in the injured liver. PPAR α activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPAR α activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPAR α activation suppressed proinflammatory responses and inhibited phosphorylated NF- κ Bp65, phosphorylated JNK and phosphorylated ERK pathways in vivo . Second, protection by PPAR α 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 α 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 α -mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.