Name
Title | ||
|---|---|---|
Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling. |
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. |
Year | DOI | Venue |
|---|---|---|
2016 | 10.1371/journal.pcbi.1004431 | PLOS COMPUTATIONAL BIOLOGY |
Field | DocType | Volume |
Downregulation and upregulation,Gene silencing,Biology,Nuclear receptor,Gene expression,MAPK/ERK pathway,Regulation of gene expression,Signal transduction,Bioinformatics,Genetics,stat | Journal | 12 |
Issue | ISSN | Citations |
1 | 1553-7358 | 0 |
PageRank | References | Authors |
0.34 | 5 | 10 |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Roland Keller | 1 | 47 | 2.83 |
| Marcus Klein | 2 | 0 | 0.34 |
| Maria Thomas | 3 | 3 | 1.12 |
| Andreas Dräger | 4 | 292 | 22.16 |
| Ute Metzger | 5 | 0 | 0.34 |
| Markus F Templin | 6 | 1 | 1.16 |
| Thomas O Joos | 7 | 0 | 0.34 |
| Wolfgang E Thasler | 8 | 13 | 1.61 |
| Andreas Zell | 9 | 23 | 2.76 |
| Ulrich M Zanger | 10 | 12 | 1.89 |