Keller, Roland and Klein, Marcus and Thomas, Maria and Dräger, Andreas and Metzger, Ute and Templin, Markus F. and Joos, Thomas O. and Thasler, Wolfgang E. and Zell, Andreas and Zanger, Ulrich M.

Coordinating role of RXRα in downregulating hepatic detoxification during inflammation revealed by fuzzy-logic modeling

PLoS Computational Biology vol. 12 (2016), no. 1, Public Library of Science, pp. e1004431


Abstract

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.


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BibTeX

@article{Keller2016a,
  author = {Keller, Roland and Klein, Marcus and Thomas, Maria and Dr\"ager,
    Andreas and Metzger, Ute and Templin, Markus F. and Joos, Thomas O. and
    Thasler, Wolfgang E. and Zell, Andreas and Zanger, Ulrich M.},
  title = {{Coordinating role of RXR$\alpha$ in downregulating hepatic
    detoxification during inflammation revealed by fuzzy-logic modeling}},
  journal = {PLoS Computational Biology},
  publisher = {Public Library of Science},
  year = {2016},
  month = jan,
  volume = {12},
  url = {http://dx.doi.org/10.1371%2Fjournal.pcbi.1004431},
  pages = {e1004431},
  number = {1},
  doi = {10.1371/journal.pcbi.1004431},
  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 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 RXR$\alpha$ playing a central role. Validation experiments
    revealed a striking similarity of RXR$\alpha$ gene silencing and IL-6
    stimulation with respect to negative gene regulation. These results concur
    with RXR$\alpha$ functioning as obligatory heterodimerization partner for
    several nuclear receptors that regulate drug and lipid metabolism.},
}