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Keller, Roland; Klein, Marcus; Thomas, Maria; Dräger, Andreas; Metzger, Ute; Templin, Markus F.; Joos, Thomas O.; Thasler, Wolfgang E.; Zell, Andreas; Zanger, Ulrich M. (2016): Coordinating Role of RXR alpha in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.
In: PLOS Computational Biology 12(1), e1004431
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Abstract

During various inflammatory processes circulating cytokines including IL-6, IL-1 beta, and TNF alpha elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXR alpha playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRa gene silencing versus IL-6 induced negative gene regulation (r(s) = 0.79;P<0.0001). These results concur with RXRa functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.