期刊
DISEASE MODELS & MECHANISMS
卷 9, 期 7, 页码 799-809出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.023242
关键词
Peroxisome proliferator-activated receptor alpha; Endoplasmic reticulum stress; Acute liver failure; Hepatotoxicity; Apoptosis
资金
- China National Key Project of the Twelfth Five-year Plan [2012ZX10002004-006, 2012ZX10004904-003-001, 2013ZX10002002-006-001]
- National Natural Science Foundation of China [81270532, 81372094, 81300349]
- Wang Boen Liver Fibrosis Research Foundation of China Foundation for Hepatitis Prevention and Control [CFHPC20131031]
- Natural Science Foundation of Beijing Municipality [7162085]
- Beijing Municipal Science & Technology Commission [Z161100000516113]
- Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality [IDHT20150502]
- High-level Technical Personnel Training Plan of the Beijing Health System [2013-3-075]
- Innovation Project Fund Designated for Graduate Student of Academic Degree Commission of Education Department, Hebei Province
Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a key regulator to ameliorate liver injury incases 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 PPAR alpha 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 PPAR alpha, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPAR alpha 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 PPAR alpha activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPAR alpha 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 PPAR alpha expression, as 4-PBA pre-treatment promoted upregulation of PPAR alpha, and inhibition of PPAR alpha by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPAR alpha activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPAR alpha inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPAR alpha activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPAR alpha could be a potential therapeutic strategy to ameliorate ALF.
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