Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells

Hyunju Cho, Ming Wu, Linxia Zhang, Ryan Thompson, Aritro Nath, Christina Chan

    Research output: Contribution to journalArticle

    • 13 Citations

    Abstract

    Background: Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2) cells and the results were used to update the model and our current understanding of the signaling induced by palmitate.Results: The three key things from the in silico simulation and experimental results are: 1) palmitate induces different signaling pathways (PKR (double-stranded RNA-activated protein kinase), PERK (PKR-like ER kinase), PKA (cyclic AMP (cAMP)-dependent protein kinase A) in a time dependent-manner, 2) both ATF4 and CREB1 (cAMP-responsive element-binding protein 1) interact with the Atf4 promoter to contribute to a prolonged accumulation of ATF4, and 3) CREB1 is involved in ER-stress induced apoptosis upon palmitate treatment, by regulating ATF4 expression and possibly Ca2+ dependent-CaM (calmodulin) signaling pathway.Conclusion: The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.

    Original languageEnglish (US)
    Article number9
    JournalBMC Systems Biology
    Volume7
    DOIs
    StatePublished - Jan 22 2013

    Profile

    Activating Transcription Factor 4
    Endoplasmic Reticulum Stress
    Palmitates
    Hep G2 Cells
    Transcription factor
    Transcription factors
    Endoplasmic reticulum
    Computer Simulation
    Apoptosis
    Signaling pathways
    Dependent
    Model
    Cell death
    eIF-2 Kinase
    Cyclic AMP-Dependent Protein Kinases
    Carrier Proteins
    Up-Regulation
    Cyclic AMP
    Protein kinase
    Protein

    Keywords

    • ATF4
    • CREB1
    • Discrete dynamic model
    • Palmitate-induced ER stress
    • Signal transduction

    ASJC Scopus subject areas

    • Molecular Biology
    • Structural Biology
    • Applied Mathematics
    • Modeling and Simulation
    • Computer Science Applications

    Cite this

    Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. / Cho, Hyunju; Wu, Ming; Zhang, Linxia; Thompson, Ryan; Nath, Aritro; Chan, Christina.

    In: BMC Systems Biology, Vol. 7, 9, 22.01.2013.

    Research output: Contribution to journalArticle

    Cho, Hyunju; Wu, Ming; Zhang, Linxia; Thompson, Ryan; Nath, Aritro; Chan, Christina / Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells.

    In: BMC Systems Biology, Vol. 7, 9, 22.01.2013.

    Research output: Contribution to journalArticle

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    abstract = "Background: Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2) cells and the results were used to update the model and our current understanding of the signaling induced by palmitate.Results: The three key things from the in silico simulation and experimental results are: 1) palmitate induces different signaling pathways (PKR (double-stranded RNA-activated protein kinase), PERK (PKR-like ER kinase), PKA (cyclic AMP (cAMP)-dependent protein kinase A) in a time dependent-manner, 2) both ATF4 and CREB1 (cAMP-responsive element-binding protein 1) interact with the Atf4 promoter to contribute to a prolonged accumulation of ATF4, and 3) CREB1 is involved in ER-stress induced apoptosis upon palmitate treatment, by regulating ATF4 expression and possibly Ca2+ dependent-CaM (calmodulin) signaling pathway.Conclusion: The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.",
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