title: Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure.
abstract: Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF.
authors.affiliation: Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang 050051, China Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Xiangying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Shi
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang 050051, China zhaocy2005@163.com duanzhongping0929@hotmail.com.
authors.forename: Caiyan
authors.identifier: 0000-0001-5997-4641
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Beijing Artificial Liver Treatment and Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China zhaocy2005@163.com duanzhongping0929@hotmail.com.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005688:Galactosamine; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D047493:PPAR alpha; D010654:Phenylbutyrates; D011743:Pyrimidines; D051742:Transcription Factor CHOP; D005688:Galactosamine; C075773:4-phenylbutyric acid; C006253:pirinixic acid
keywords: Acute liver failure; Apoptosis; Endoplasmic reticulum stress; Hepatotoxicity; Peroxisome proliferator-activated receptor α