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X Demographics
Mendeley readers
Attention Score in Context
| Title |
Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8
|
|---|---|
| Published in |
Frontiers in Pharmacology, November 2015
|
| DOI | 10.3389/fphar.2015.00261 |
| Pubmed ID | |
| Authors |
Maria Thomas, Stefan Winter, Britta Klumpp, Miia Turpeinen, Kathrin Klein, Matthias Schwab, Ulrich M. Zanger |
| Abstract |
The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ∼60 and ∼50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype. |
X Demographics
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| France | 1 | 50% |
| Switzerland | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 34 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 18% |
| Student > Master | 5 | 15% |
| Student > Ph. D. Student | 5 | 15% |
| Professor > Associate Professor | 4 | 12% |
| Other | 2 | 6% |
| Other | 1 | 3% |
| Unknown | 11 | 32% |
| Readers by discipline | Count | As % |
|---|---|---|
| Pharmacology, Toxicology and Pharmaceutical Science | 4 | 12% |
| Biochemistry, Genetics and Molecular Biology | 4 | 12% |
| Physics and Astronomy | 3 | 9% |
| Medicine and Dentistry | 3 | 9% |
| Agricultural and Biological Sciences | 2 | 6% |
| Other | 5 | 15% |
| Unknown | 13 | 38% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 November 2015.
All research outputs
#18,430,119
of 22,832,057 outputs
Outputs from Frontiers in Pharmacology
#8,235
of 16,070 outputs
Outputs of similar age
#205,240
of 285,322 outputs
Outputs of similar age from Frontiers in Pharmacology
#53
of 94 outputs
Altmetric has tracked 22,832,057 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 16,070 research outputs from this source. They receive a mean Attention Score of 4.9. This one is in the 37th percentile – i.e., 37% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 285,322 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 16th percentile – i.e., 16% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 94 others from the same source and published within six weeks on either side of this one. This one is in the 22nd percentile – i.e., 22% of its contemporaries scored the same or lower than it.