title: Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway.
abstract: Peroxisome proliferator-activated receptor α (PPARα) 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 PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα 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, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα 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 PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.
authors.affiliation: 1] Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China [2] Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Jiao
authors.affiliation: 1] Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China [2] Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Ren
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Wen
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Shi
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sichuan University, The College of Life Sciences, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Duan
mesh_terms: D000208:Acute Disease; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D006509:Hepatitis B / Q000150:complications / Q000175:diagnosis; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017093:Liver Failure / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D047493:PPAR alpha; D020011:Protective Agents; D011743:Pyrimidines; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C025946:3-methyladenine; D005688:Galactosamine; C006253:pirinixic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000071193:Autophagy-Related Protein 7; D000225:Adenine