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The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARα-tr, autonomously regulates proliferative and pro-inflammatory genes

Overview of attention for article published in BMC Cancer, June 2015
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Title
The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARα-tr, autonomously regulates proliferative and pro-inflammatory genes
Published in
BMC Cancer, June 2015
DOI 10.1186/s12885-015-1500-x
Pubmed ID
Authors

Maria Thomas, Christine Bayha, Kathrin Klein, Simon Müller, Thomas S. Weiss, Matthias Schwab, Ulrich M. Zanger

Abstract

The peroxisome proliferator-activated receptor alpha (PPARα) controls lipid/energy homeostasis and inflammatory responses. The truncated splice variant PPARα-tr was suggested to exert a dominant negative function despite being unable to bind consensus PPARα DNA response elements. The distribution and variability factor of each PPARα variant were assessed in the well-characterized cohort of human liver samples (N = 150) on the mRNA and protein levels. Specific siRNA-mediated downregulation of each transcript as well as specific overexpression with subsequent qRT-PCR analysis of downstream genes was used for investigation of specific functional roles of PPARα-wt and PPARα-tr forms in primary human hepatocytes. Bioinformatic analyses of genome-wide liver expression profiling data suggested a possible role of PPARα-tr in downregulating proliferative and pro-inflammatory genes. Specific gene silencing of both forms in primary human hepatocytes showed that induction of metabolic PPARα-target genes by agonist WY14,643 was prevented by PPARα-wt knock-down but neither prevented nor augmented by PPARα-tr knock-down. WY14,643 treatment did not induce proliferative genes including MYC, CDK1, and PCNA, and knock-down of PPARα-wt had no effect, while PPARα-tr knock-down caused up to 3-fold induction of these genes. Similarly, induction of pro-inflammatory genes IL1B, PTGS2, and CCL2 by IL-6 was augmented by knock-down of PPARα-tr but not of PPARα-wt. In contrast to human proliferative genes, orthologous mouse genes were readily inducible by WY14,643 in PPARα-tr non-expressing AML12 mouse hepatocytes. Induction was augmented by overexpression of PPARα-wt and attenuated by overexpression of PPARα-tr. Pro-inflammatory genes including IL-1β, CCL2 and TNFα were induced by WY14,643 in mouse and human cells and both PPARα forms attenuated induction. As potential mechanism of PPARα-tr inhibitory action we suggest crosstalk with WNT/β-catenin pathway. Finally, treatment with WY14,643 in the presence of PPARα-tr resulted in the significant reduction of cell viability of AML12 and human ovarian cancer cell line, SKOV3. Our data suggest that the truncated PPARα splice variant functions as an endogenous inhibitor of proliferative and pro-inflammatory genes in human cells and that its absence in mouse may explain species-specific differences in fibrate-induced hepatocarcinogenesis.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 18 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 18 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 4 22%
Student > Master 3 17%
Student > Bachelor 2 11%
Student > Postgraduate 2 11%
Researcher 1 6%
Other 1 6%
Unknown 5 28%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 44%
Agricultural and Biological Sciences 3 17%
Veterinary Science and Veterinary Medicine 1 6%
Medicine and Dentistry 1 6%
Neuroscience 1 6%
Other 0 0%
Unknown 4 22%

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 29 June 2015.
All research outputs
#5,064,224
of 6,815,308 outputs
Outputs from BMC Cancer
#1,998
of 3,144 outputs
Outputs of similar age
#153,176
of 223,215 outputs
Outputs of similar age from BMC Cancer
#137
of 165 outputs
Altmetric has tracked 6,815,308 research outputs across all sources so far. This one is in the 14th percentile – i.e., 14% of other outputs scored the same or lower than it.
So far Altmetric has tracked 3,144 research outputs from this source. They receive a mean Attention Score of 3.2. This one is in the 21st percentile – i.e., 21% of its peers scored the same or lower than it.
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We're also able to compare this research output to 165 others from the same source and published within six weeks on either side of this one. This one is in the 6th percentile – i.e., 6% of its contemporaries scored the same or lower than it.