Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling


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

help Authors

[Roland Keller] [Marcus Klein] [Maria Thomas] [Andreas Dräger] [Thomas Joos]

help Attributions


help Scales

Views: 1541
  • Created: 7th Jan 2016 at 15:20
  • Last updated: 7th Jan 2016 at 15:24

Related items


Log in / Register

Need an account?
Sign up

Forgotten password?

Front Page

Virtual Liver Network


Related Projects and friends

Imprint Taverna workflow workbench myExperiment JWS Online ISATAB myGrid Sabio-RK BioPortal Semantic SBML

Powered by:


Silk icons 1.3
Crystal Clear icons

Virtual Liver Seek uses one essential cookie to keep you session open and one cookie to keep your consent.

By continuing to use this site you agree to the use of cookies