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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 <jats:italic>in silico<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The three key things from the <jats:italic>in silico<\/jats:italic> 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 <jats:italic>Atf4<\/jats:italic> 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 Ca<jats:sup>2+<\/jats:sup> dependent-CaM (calmodulin) signaling pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The <jats:italic>in silico<\/jats:italic> model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-7-9","type":"journal-article","created":{"date-parts":[[2013,1,22]],"date-time":"2013-01-22T11:15:17Z","timestamp":1358853317000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells"],"prefix":"10.1186","volume":"7","author":[{"given":"Hyunju","family":"Cho","sequence":"first","affiliation":[]},{"given":"Ming","family":"Wu","sequence":"additional","affiliation":[]},{"given":"Linxia","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Ryan","family":"Thompson","sequence":"additional","affiliation":[]},{"given":"Aritro","family":"Nath","sequence":"additional","affiliation":[]},{"given":"Christina","family":"Chan","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2013,1,22]]},"reference":[{"issue":"2\u20133","key":"1033_CR1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/S1388-1981(02)00342-6","volume":"1585","author":"RH Unger","year":"2002","unstructured":"Unger RH, Orci L: Lipoapoptosis: its mechanism and its diseases. 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