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| Status |
Public on Sep 11, 2009 |
| Title |
Gender-specific gene repression of PPAR-alpha KO mice in liver and heart |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Most metabolic studies are conducted in male animals; thus, the molecular mechanism controlling gender-specific pathways has been neglected, including sex-dependent responses to peroxisome proliferator-activated receptors (PPARs). Here we show that PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and inflammation. In males, this effect is reproduced by the administration of synthetic PPARalpha ligand. Using the steroid hydroxylase gene Cyp7b1 as a model, we elucidated the molecular mechanism of this PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggers the interaction of PPARalpha with the GA-binding protein alpha bound to the target promoter. Histone deacetylase is then recruited, and histones and adjacent Sp1-binding site are methylated. These events result in the loss of Sp1-stimulated expression, and thus the down-regulation of Cyp7b1. Physiologically, this repression confers protection against estrogen-induced intrahepatic cholestasis, paving the way for a novel therapy against the most common hepatic disease during pregnancy.
Keywords: Genetic modification
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| Overall design |
Expression profile difference between male and female PPARalpha wild-type and knock-out mice in liver and heart (3 pools of 4 animals in each group). Wild-type (12 males and 12 females) and knock-out PPARalpha SV129 mice (12 males and 12 females) approximately 10 to 12 weeks of age were killed at ZT14 and their livers and hearts quickly removed and frozen.
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| Contributor(s) |
Leuenberger N, Pradervand S, Wahli W |
| Citation(s) |
19729835 |
| |
| Submission date |
Jan 13, 2009 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Sylvain Pradervand |
| E-mail(s) |
Sylvain.Pradervand@unil.ch
|
| Phone |
+41 21 692 39 08
|
| Organization name |
UNI Lausanne
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| Department |
CIG
|
| Lab |
DNA Array Facility
|
| Street address |
Genopode
|
| City |
Lausanne |
| ZIP/Postal code |
1015 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA111369 |
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