Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

Sharon Ann Barretto
ORCID logo ,
Frederic Lasserre
,
Anne Fougerat
,
Lorraine Smith
,
Tiffany Fougeray
,
Celine Lukowicz
,
Arnaud Polizzi
,
Sarra Smati
,
Marion Régnier
,
Claire Naylies
,
Colette Betoulieres
,
Yannick Lippi
ORCID logo ,
hervé guillou
ORCID logo ,
Nicolas Loiseau
ORCID logo ,
Laurence Payrastre
,
Laila Lakhal
,
Sandrine Ellero-Simatos
* ORCID logo
Version 1 : Received: 21 June 2019 / Approved: 3 July 2019 / Online: 3 July 2019 (15:08:03 CEST)

A peer-reviewed article of this Preprint also exists.

Barretto, S.A.; Lasserre, F.; Fougerat, A.; Smith, L.; Fougeray, T.; Lukowicz, C.; Polizzi, A.; Smati, S.; Régnier, M.; Naylies, C.; Bétoulières, C.; Lippi, Y.; Guillou, H.; Loiseau, N.; Gamet-Payrastre, L.; Mselli-Lakhal, L.; Ellero-Simatos, S. Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. Int. J. Mol. Sci. 2019, 20, 3767. Barretto, S.A.; Lasserre, F.; Fougerat, A.; Smith, L.; Fougeray, T.; Lukowicz, C.; Polizzi, A.; Smati, S.; Régnier, M.; Naylies, C.; Bétoulières, C.; Lippi, Y.; Guillou, H.; Loiseau, N.; Gamet-Payrastre, L.; Mselli-Lakhal, L.; Ellero-Simatos, S. Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. Int. J. Mol. Sci. 2019, 20, 3767.

Abstract

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes mostly xenobiotic metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

Keywords

nuclear receptors; hepatokines; transcriptomics

Subject

Biology and Life Sciences, Endocrinology and Metabolism

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF Download Supplementary

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Supplementary Files Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.