Analysis of the heat shock response in mouse liver reveals dependence on the Nuclear Receptor Peroxisome Proliferator-Activated Receptor alpha (PPARalpha)

B. Vallanat, S.P. Anderson, H.M. Brown-Borg, H. Ren, A.H. Kersten, S. Jonnalagadda, S. Srinivasan, J.C. Corton

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

Background - The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) 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 PPARa and the HS response mediated by HSF1. Results - Wild-type and PPARa-null mice were exposed to HS, the PPARa 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 PPARa-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARa-null mice that are known targets of PPAR¿ co-activator-1 (PGC-1) family members. Pretreatment of PPARa-null mice with WY increased expression of PGC-1ß 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 PPARa and HSF1, a number require both factors for HS responsiveness. Conclusions - These findings demonstrate that the PPARa genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARa in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS
Original languageEnglish
Article number16
Number of pages15
JournalBMC Genomics
Volume11
DOIs
Publication statusPublished - 2010

Keywords

  • gene-expression
  • molecular chaperones
  • caloric restriction
  • stress-proteins
  • null mice
  • protection
  • pgc-1-beta
  • cells
  • coactivator
  • clofibrate

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