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

Abstract

BackgroundThe 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.ResultsWild-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.ConclusionsThese 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.

Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts

“…SFN induces several cellular protective mechanisms, including induction of the Keap1-Nrf2 pathway (Baird & Dinkova-Kostova, 2011 ). Moreover, SFN has been shown to enhance proteasome activity by upregulating several proteasomal subunits and Hsp proteins (Gan et al ., 2010 ; Vallanat et al ., 2010 ). Consistently, we report that SFN treatment of HGPS cells increased the expression of components of the proteasome system and of several Hsps and cochaperones, thereby increasing proteasome activity and autophagy.…”

Impact of heat shock transcription factor 1 on global gene expression profiles in cells which induce either cytoprotective or pro-apoptotic response following hyperthermia

“…The changes in the global gene expression profiles following heat shock were already studied in different organisms (from bacteria to mammals), and in different types of cells or tissues [8,40-46], even in mouse liver [45] and testes [47-49]. Although some differences in heat shock response between somatic cells exist, in all of them pro-survival signaling pathways are activated.…”

Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

“…Conversely, hepatic Nrf2 mRNA is increased by fasting [31,32], although whether this is mediated by PPARa is not known. Interestingly, a number of heat shock-regulated genes, such as Dnaja1, require both Hsf1 and PPARa for transcriptional activation [33]. Together, these findings suggest another level of common Hsf1 and Nrf2 influence -modulation of the activity of nuclear receptors.…”