The transcription factor CHOP, a central component of the transcriptional regulatory network induced upon CCl4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity
Author
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Campos, Gisela
Author
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Schmidt Heck, Wolfgang
es_CL
Author
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Ghallab, Ahmed
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Author
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Rochlitz, Katharina
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Author
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Putter, Larissa
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Author
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Medinas Bilches, Danilo
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Author
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Hetz Flores, Claudio
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Author
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Widera, Agata
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Author
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Cadenas, Cristina
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Author
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Begher-Tibbe, Brigitte
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Author
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Reif, Raymond
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Author
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Gunther, Georgia
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Author
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Sachinidis, Agapios
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Author
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Hengstler, Jan G.
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Author
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Godoy, Patricio
es_CL
Admission date
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2015-01-07T18:49:59Z
Available date
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2015-01-07T18:49:59Z
Publication date
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2014
Cita de ítem
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Arch Toxicol (2014) 88:1267–1280
en_US
Identifier
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DOI 10.1007/s00204-014-1240-8
Identifier
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https://repositorio.uchile.cl/handle/2250/129602
General note
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Artículo de publicación ISI
en_US
Abstract
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Since xenobiotics enter the organism via the
liver, hepatocytes must cope with numerous perturbations,
including modifications of proteins leading to endoplasmic
reticulum stress (ER-stress). This triggers a signaling
pathway termed unfolded protein response (UPR)
that aims to restore homeostasis or to eliminate disturbed
hepatocytes by apoptosis. In the present study, we used
the well-established CCl4 hepatotoxicity model in mice to
address the questions whether CCl4 induces ER-stress and,
if so, whether the well-known ER-stress effector CHOP
is responsible for CCl4-induced apoptosis. For this purpose,
we treated mice with a high dose of CCl4 injected
i.p. and followed gene expression profile over time using
Affymetrix gene array analysis. This time resolved gene expression analysis allowed the identification of gene clusters
with overrepresented binding sites for the three most
important ER-stress induced transcription factors, CHOP,
XBP1 and ATF4. Such result was confirmed by the demonstration
of CCl4-induced XBP1 splicing, upregulation
of CHOP at mRNA and protein levels, and translocation
of CHOP to the nucleus. Two observations indicated that
CHOP may be responsible for CCl4-induced cell death: (1)
Nuclear translocation of CHOP was exclusively observed
in the pericentral fraction of hepatocytes that deteriorate in
response to CCl4 and (2) CHOP-regulated genes with previously
reported pro-apoptotic function such as GADD34,
TRB3 and ERO1L were induced in the pericentral zone as
well. Therefore, we compared CCl4 induced hepatotoxicity
in CHOP knockout versus wild-type mice. Surprisingly,
genetic depletion of CHOP did not afford protection against
CCl4-induced damage as evidenced by serum GOT and GPT as well as quantification of dead tissue areas. The negative
result was obtained at several time points (8, 24 and
72 h) and different CCl4 doses (1.6 and 0.132 g/kg). Overall,
our results demonstrate that all branches of the UPR
are activated in mouse liver upon CCl4 treatment. However,
CHOP does not play a critical role in CCl4-induced
cell death and cannot be considered as a biomarker strictly
linked to hepatotoxicity. The role of alternative UPR effectors
such as XBP1 remains to be investigated.
en_US
Patrocinador
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This study was supported by the SEURAT-1 projects
NOTOX (EU-project FP7-Health Grant Agreement No. 267038)
and DETECTIVE (EU-project FP7-Health Grant Agreement No.
266838) and the BMBF (German Federal Ministry of Education and
Research) project Virtual Liver (0313854). We acknowledge support
from FONDECYT (1140549), Millennium Institute (P09-015-F), Ring
Initiative (ACT1109) (to C.H.), and FONDECYT (3130351 to D.B.M.).
The transcription factor CHOP, a central component of the transcriptional regulatory network induced upon CCl4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity