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    Endoplasmic reticulum stress-induced CHOP inhibits PGC-1α and causes mitochondrial dysfunction in diabetic embryopathy

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    Author
    Chen, X.
    Zhong, J.
    Dong, D.
    Date
    2017
    Journal
    Toxicological Sciences
    Publisher
    Oxford University Press
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1093/toxsci/kfx096
    Abstract
    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-γ coactivator-1α (PGC-1α), an essential regulator for mitochondrial biogenesis and function. Both CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed PGC-1α expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1α by high glucose. In response to the ER stress inducer tunicamycin, PGC-1α expression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid blocked high glucose-suppressed PGC-1α expression. Moreover, maternal diabetes in vivo and high glucose in vitro promoted the interaction between CHOP and the PGC-1α transcriptional regulator CCAAT/enhancer binding protein-β (C/EBPβ), and reduced C/EBPβ binding to the PGC-1α promoter leading to markedly decrease in PGC-1α expression. Together, our findings support the hypothesis that maternal diabetes-induced ER stress increases CHOP expression which represses PGC-1α through suppressing the C/EBPβ transcriptional activity, subsequently induces mitochondrial dysfunction and ultimately results in NTDs. Copyright The Author 2017.
    Sponsors
    NIH (R01DK083243, R01DK101972, R01HL131737, and R01DK103024).
    Keyword
    C/EBPβ
    CHOP
    Diabetic embryopathy
    ER stress
    Mitochondrial dysfunction
    Neural tube defects
    PGC-1α
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028298346&doi=10.1093%2ftoxsci%2fkfx096&partnerID=40&md5=40e2a22b5b08fc8da6f74c50996420c5; http://hdl.handle.net/10713/11269
    ae974a485f413a2113503eed53cd6c53
    10.1093/toxsci/kfx096
    Scopus Count
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    UMB Open Access Articles 2017

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