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

• Published in: Cell death & disease Vol. 5; no. 8; p. e1397
• Main Authors: Jiao, M, Ren, F, Zhou, L, Zhang, X, Zhang, L, Wen, T, Wei, L, Wang, X, Shi, H, Bai, L, Zheng, S, Zhang, J, Chen, Y, Han, Y, Zhao, C, Duan, Z
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2014; Nature Publishing Group
• Subjects: 631/250/256; 631/80/82/39; 631/80/86; 692/699/1503/1607; Acute Disease; Adenine - analogs & derivatives; Adenine - pharmacology; Adult; Animals; Antibodies; Autophagy - drug effects; Autophagy-Related Protein 7; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cells, Cultured; Chemokines - metabolism; Cytokines - metabolism; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Galactosamine - toxicity; Hepatitis B - complications; Hepatitis B - diagnosis; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Immunology; Inflammation; JNK Mitogen-Activated Protein Kinases - metabolism; Life Sciences; Lipopolysaccharides - toxicity; Liver Failure - chemically induced; Liver Failure - drug therapy; Liver Failure - pathology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Middle Aged; Original; original-article; Phosphorylation - drug effects; PPAR alpha - antagonists & inhibitors; PPAR alpha - genetics; PPAR alpha - metabolism; Protective Agents - pharmacology; Protective Agents - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; RNA Interference; RNA, Small Interfering - metabolism; Toll-Like Receptor 4 - metabolism; Transcription Factor RelA - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.361

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.