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Open Access Research article

Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor α (PPARα)

Beena Vallanat1, Steven P Anderson2, Holly M Brown-Borg3, Hongzu Ren1, Sander Kersten4, Sudhakar Jonnalagadda5, Rajagopalan Srinivasan56 and J Christopher Corton1*

Author Affiliations

1 NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, USA

2 Safety Assessment, Merial, Ltd., Duluth, GA 30096, USA

3 Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58203-2817, USA

4 Nutrition, Metabolism and Genomics Group, Wageningen University and Nutrigenomics Consortium, TI Food and Nutrition, Wageningen, the Netherlands

5 Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore

6 Department of Chemical and Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore

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BMC Genomics 2010, 11:16  doi:10.1186/1471-2164-11-16

Published: 7 January 2010

Abstract

Background

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS) through activation by HS factor-1 (HSF1). We hypothesized that there are interactions on a genetic level between PPARα and the HS response mediated by HSF1.

Results

Wild-type and PPARα-null mice were exposed to HS, the PPARα agonist WY-14,643 (WY), or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARα-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARα-null mice that are known targets of PPARγ co-activator-1 (PGC-1) family members. Pretreatment of PPARα-null mice with WY increased expression of PGC-1β and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1-null mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARα and HSF1, a number require both factors for HS responsiveness.

Conclusions

These findings demonstrate that the PPARα genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARα in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.