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Nevertheless the mechanisms underlying these adverse effects are incompletely understood. In this study, we determined the effect of relatively short (3\u00a0h) or prolonged (72\u00a0h) exposure to VPA on mitochondrial function in primary human hepatocytes (PHHs). While 3\u00a0h VPA exposure did not affect oxygen consumption rates (OCRs) in PHHs, prolonged exposure (24\u201372\u00a0h) significantly reduced basal and maximal OCRs. Given that in particular prolonged VPA exposure is required to cause mitochondrial dysfunction, we investigated gene expression data after VPA exposure for 24, 48, 72\u00a0h and 72\u00a0h VPA followed by a 72\u00a0h washout period. We were able to reduce the comprehensive gene expression changes into a more comprehensible set of 18 TFs that were predicted to be persistently activated after 72\u00a0h of VPA exposure. Lentiviral knock-down of one of the candidate TFs, C\/EBP\u03b1, partly rescued VPA-induced mitochondrial dysfunction. Furthermore, RNA-Seq analysis of shC\/EBP\u03b1 and shGFP control PHHs identified 24 genuine C\/EBP\u03b1 target genes that are regulated in response to prolonged VPA exposure in PHHs. Altogether this provides new insights on the involvement of C\/EBP\u03b1 in driving VPA-induced mitochondrial dysfunction in human liver cells. This hub gene, with its downstream regulators involved in this deregulation, thus represent potential new biomarkers for VPA-induced mitochondrial dysfunction.<\/jats:p>","DOI":"10.1007\/s00204-020-02835-x","type":"journal-article","created":{"date-parts":[[2020,7,4]],"date-time":"2020-07-04T05:02:52Z","timestamp":1593838972000},"page":"3463-3473","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Valproic acid promotes mitochondrial dysfunction in primary human hepatocytes in vitro; impact of C\/EBP\u03b1-controlled gene expression"],"prefix":"10.1007","volume":"94","author":[{"given":"F.","family":"Caiment","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Wolters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Schrooders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Kleinjans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-7558","authenticated-orcid":false,"given":"T.","family":"van den Beucken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,4]]},"reference":[{"issue":"29","key":"2835_CR1","doi-asserted-by":"publisher","first-page":"26293","DOI":"10.1074\/jbc.M202301200","volume":"277","author":"G Behre","year":"2002","unstructured":"Behre G, Singh SM, Liu H et al (2002) Ras signaling enhances the activity of C\/EBP\u03b1 to induce granulocytic differentiation by phosphorylation of serine 248. 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