title: [Role of endoplasmic reticulum stress in D-GalN/LPS-induced acute liver failure].
abstract: OBJECTIVE
  To study the role of endoplasmic reticulum stress (ERS) in acute liver failure (ALF) using a mouse model of D-Galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF.
  
  
  METHODS
  The ALF model was established by administering intraperitoneal (i.p.) injections of D-Ga1N (700 mg/kg) and LPS (10 mug/kg) to six C57BL/6 mice. Three of the modeled mice were also administered 4-phenylbutyrate (4-PBA; 100 mg/kg i.p.) at 6 hours before the onset of ALF and served as the intervention group. Non-modeled mice served as controls. All mice were analyzed by western blotting and qRT-PCR to determine the expression levels of ERS-related proteins in liver tissue. Liver function was assessed by measuring levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum. Extent of injury to the liver tissue was assessed by hematoxylin-eosin staining and histological analysis. qRT-PCR was also used to detect differences in expression of inflammation-related genes, and western blotting was also used to detect differences in expression of the apoptosis related protein Caspase-3.The extent of apoptosis in liver tissue was assessed by TUNEL assay.
  
  
  RESULTS
  The ERS markers GRP78 and GRP94 showed increased expression at both the gene and protein levels which followed progression of ALF. The ERS effector proteins XBP-1, ATF-6 and IRE 1 a involved in the unfolded protein response were activated in the early stages of ALF, and the ERS-induced apoptosis regulators Caspase-12 and CHOP were activated in the late stage of ALF. Inhibition of ERS by 4-PBA intervention protected against injury to liver tissue and function, as evidenced by significantly lower levels of serum ALT and AST and a remarkably decreased extent of histological alterations. Furthermore, the inhibition of ERS suppressed expression of the proinflammatory cytokines TNFa, IL-6 and IL-1 β, and reduced the extent of hepatocyte apoptosis.
  
  
  CONCLUSIONS
  ERS is activated in the mouse model of D-GalN/LPS-induced ALF. Inhibition of ERS may be protective against liver injury and the mechanism of action may involve reductions in inflammatory and apoptotic factors and/or signaling. Therefore, inhibiting ERS may represent a novel therapeutic approach for treating ALF.
authors.affiliation: Institute of hepatology, Beijing You'an hospital, Capital Medical University, beijing 100069, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Bingzhang
authors.initials: B
authors.lastname: Yang
authors.forename: Xiangying
authors.initials: X
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.forename: Jiming
authors.initials: J
authors.lastname: Yin
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Piao
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005688:Galactosamine / Q000009:adverse effects; D008070:Lipopolysaccharides / Q000009:adverse effects; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D005688:Galactosamine