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

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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.

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

Profile

Activating Transcription Factor 4
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Transcription factors
Palmitates
Hep G2 Cells
Transcription Factor
Apoptosis
Signaling Pathways
Cell death
Cell
Cyclic AMP
Protein Kinase
Computer Simulation
eIF-2 Kinase
Dependent
Cyclic AMP-Dependent Protein Kinases
Calmodulin
Carrier Proteins
Palmitic acid

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. 2013 ; Vol. 7.
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