title: Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells.
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.
  
  
  CONCLUSIONS
  The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.
authors: Department of Chemical Engineering and Materials Science, East Lansing, MI 48824, USA.
authors: Hyunju
authors: H
authors: Cho
authors: Ming
authors: M
authors: Wu
authors: Linxia
authors: L
authors: Zhang
authors: Ryan
authors: R
authors: Thompson
authors: Aritro
authors: A
authors: Nath
authors: Christina
authors: C
authors: Chan
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D003198:Computer Simulation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D019308:Palmitic Acid / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C497109:ATF4 protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; D019308:Palmitic Acid