Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling
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During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the downregulation of many drug metabolizing enzymes and transporters but it remained unclear, whether a common mechanism is involved. To address this question 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. The extensive data sets were used to calibrate a prior knowledge-based fuzzy-logic model comprising signal transduction and gene regulation. Our model suggests a major role of MAPK and PI3K signaling, with the orphan nuclear receptor RXRα playing a central role. Validation experiments revealed a striking similarity of RXRα gene silencing and IL-6 stimulation with respect to negative gene regulation. These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.
Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes
PLoS Comput Biol
PLoS Comput Biol 12(1) : e1004431
4th Jan 2016
Roland Keller, Marcus Klein, Maria Thomas, Andreas Dräger, Ute Metzger, Markus F. Templin, Thomas O. Joos, Wolfgang E. Thasler, Andreas Zell, Ulrich M. Zanger
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- Created: 7th Jan 2016 at 15:20
- Last updated: 7th Jan 2016 at 15:24
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