PMID- 28482072
OWN - NLM
STAT- MEDLINE
DCOM- 20180604
LR  - 20200730
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 158
IP  - 2
DP  - 2017 Aug 1
TI  - Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1alpha and Causes 
      Mitochondrial Dysfunction in Diabetic Embryopathy.
PG  - 275-285
LID - 10.1093/toxsci/kfx096 [doi]
AB  - Endoplasmic reticulum (ER) stress has been implicated in the development of 
      maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP 
      homologous protein (CHOP) plays an important role in the pro-apoptotic execution 
      pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced 
      neuroepithelium cell apoptosis in diabetic embryopathy is still unclear. Deletion 
      of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP 
      deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and 
      neuroepithelium cell apoptosis. Further analysis demonstrated that CHOP repressed 
      the expression of peroxisome-proliferator-activated receptor-gamma coactivator-1alpha 
      (PGC-1alpha), an essential regulator for mitochondrial biogenesis and function. Both 
      CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed 
      PGC-1alpha expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1alpha 
      by high glucose. In response to the ER stress inducer tunicamycin, PGC-1alpha 
      expression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid 
      blocked high glucose-suppressed PGC-1alpha expression. Moreover, maternal diabetes in 
      vivo and high glucose in vitro promoted the interaction between CHOP and the 
      PGC-1alpha transcriptional regulator CCAAT/enhancer binding protein-beta (C/EBPbeta), and 
      reduced C/EBPbeta binding to the PGC-1alpha promoter leading to markedly decrease in 
      PGC-1alpha expression. Together, our findings support the hypothesis that maternal 
      diabetes-induced ER stress increases CHOP expression which represses PGC-1alpha 
      through suppressing the C/EBPbeta transcriptional activity, subsequently induces 
      mitochondrial dysfunction and ultimately results in NTDs.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Chen, Xi
AU  - Chen X
AD  - Center for Translational Research, Shanghai Pulmonary Hospital, Tongji University 
      School of Medicine, Shanghai 200433, People's Republic of China.
AD  - Department of Obstetrics, Gynecology & Reproductive Sciences.
FAU - Zhong, Jianxiang
AU  - Zhong J
AD  - Department of Obstetrics, Gynecology & Reproductive Sciences.
FAU - Dong, Daoyin
AU  - Dong D
AD  - Department of Obstetrics, Gynecology & Reproductive Sciences.
FAU - Liu, Gentao
AU  - Liu G
AD  - Center for Translational Research, Shanghai Pulmonary Hospital, Tongji University 
      School of Medicine, Shanghai 200433, People's Republic of China.
FAU - Yang, Peixin
AU  - Yang P
AD  - Center for Translational Research, Shanghai Pulmonary Hospital, Tongji University 
      School of Medicine, Shanghai 200433, People's Republic of China.
AD  - Department of Biochemistry and Molecular Biology, University of Maryland School 
      of Medicine, Baltimore, Maryland 21201.
LA  - eng
GR  - R01 DK101972/DK/NIDDK NIH HHS/United States
GR  - R01 HL118491/HL/NHLBI NIH HHS/United States
GR  - R01 HL131737/HL/NHLBI NIH HHS/United States
GR  - R01 DK103024/DK/NIDDK NIH HHS/United States
GR  - R01 HL139060/HL/NHLBI NIH HHS/United States
GR  - R01 DK083243/DK/NIDDK NIH HHS/United States
GR  - R01 HL134368/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics
MH  - Cell Line
MH  - Diabetes, Gestational/*physiopathology
MH  - Dimerization
MH  - Endoplasmic Reticulum Stress/*physiology
MH  - Female
MH  - Fetal Diseases/*physiopathology
MH  - Gene Expression Regulation/drug effects
MH  - Glucose/administration & dosage
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/*physiology
MH  - Neural Tube Defects/genetics
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*antagonists 
      & inhibitors
MH  - Pregnancy
MH  - Transcription Factor CHOP/genetics/*physiology
MH  - Tunicamycin/pharmacology
PMC - PMC5837255
OTO - NOTNLM
OT  - C/EBPbeta
OT  - CHOP
OT  - ER stress
OT  - PGC-1alpha
OT  - diabetic embryopathy
OT  - mitochondrial dysfunction
OT  - neural tube defects
EDAT- 2017/05/10 06:00
MHDA- 2018/06/05 06:00
PMCR- 2018/08/01
CRDT- 2017/05/09 06:00
PHST- 2017/05/10 06:00 [pubmed]
PHST- 2018/06/05 06:00 [medline]
PHST- 2017/05/09 06:00 [entrez]
PHST- 2018/08/01 00:00 [pmc-release]
AID - 3804411 [pii]
AID - kfx096 [pii]
AID - 10.1093/toxsci/kfx096 [doi]
PST - ppublish
SO  - Toxicol Sci. 2017 Aug 1;158(2):275-285. doi: 10.1093/toxsci/kfx096.