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Open Access Highly Accessed Research article

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

Hyunju Cho1, Ming Wu2, Linxia Zhang1, Ryan Thompson3, Aritro Nath4 and Christina Chan12345*

Author Affiliations

1 Department of Chemical Engineering and Materials Science, East Lansing, MI 48824, USA

2 Department of Computer Science and Engineering, East Lansing, MI 48824, USA

3 Cell and Molecular Biology Program, East Lansing, MI, 48824, USA

4 Genetics program, East Lansing, MI, 48824, USA

5 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA

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BMC Systems Biology 2013, 7:9  doi:10.1186/1752-0509-7-9

Published: 22 January 2013

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.

Keywords:
ATF4; Palmitate-induced ER stress; CREB1; Discrete dynamic model; Signal transduction