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

Vallanat B, Anderson SP, Brown-Borg HM, Ren H, Kersten S, Jonnalagadda S, Srinivasan R, Corton JC - BMC Genomics (2010)

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

View Article: PubMed Central - HTML - PubMed

Affiliation: NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, USA. corton.chris@epa.gov

ABSTRACT

Background: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha and the HS response mediated by HSF1.

Results: Wild-type and PPARalpha- mice were exposed to HS, the PPARalpha 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 PPARalpha-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARalpha- mice that are known targets of PPARgamma co-activator-1 (PGC-1) family members. Pretreatment of PPARalpha- mice with WY increased expression of PGC-1beta 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- mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARalpha and HSF1, a number require both factors for HS responsiveness.

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

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Related in: MedlinePlus

PPARα-independent changes in triglyceride levels and fatty acid metabolism genes by heat shock. A. Serum levels of alkaline phosphatase, glucose and triglycerides 4 and 24 hrs after HS. B. Decreases in fatty acid metabolism genes by HS in wild-type and PPARα- mice. Genes called as significantly altered between control and HS groups were extracted from GSEA gene sets HSA03320_PPAR_SIGNALING_PATHWAY (wild-type mice) and HSA00071_FATTY_ACID_METABOLISM (PPARα- mice).
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Figure 3: PPARα-independent changes in triglyceride levels and fatty acid metabolism genes by heat shock. A. Serum levels of alkaline phosphatase, glucose and triglycerides 4 and 24 hrs after HS. B. Decreases in fatty acid metabolism genes by HS in wild-type and PPARα- mice. Genes called as significantly altered between control and HS groups were extracted from GSEA gene sets HSA03320_PPAR_SIGNALING_PATHWAY (wild-type mice) and HSA00071_FATTY_ACID_METABOLISM (PPARα- mice).

Mentions: We examined the levels of a number of clinical chemistry markers including triglycerides in the blood from mice 4 or 24 hrs after HS. The levels of alkaline phosphatase were increased in all WY-treated wild-type mice but not PPARα- mice (Figure 3A), paralleling the increases in gene expression for alkaline phosphatase, liver/bone/kidney (Alpl) after exposure to WY and other PPC (data not shown). Consistent with PPARα agonists playing a role in glucose homeostasis [34,35], glucose levels were lower in wild-type but not PPARα- WY-treated mice at 4 and 24 hrs. HS also lowered glucose levels in wild-type but not PPARα- mice at 24 hrs. HS did not induce overt liver damage as measured by ALT levels; minor increases were observed by HS+WY treatment in wild-type but not PPARα- mice at 4 and 24 hrs that approached significance (data not shown). These results were consistent with a lack of pathological findings in the liver. In wild-type mice triglyceride levels were increased by HS and decreased by WY at 4 hrs with no change by both treatments. At 24 hrs, triglyceride levels were decreased by HS, WY or HS+WY in wild-type mice and by HS or HS+WY in PPARα- mice. Despite uniform increases in cholesterol biosynthetic genes after WY exposure that were reversed by WY+HS treatment (Additional File 8 and 9), no changes in circulating cholesterol were noted between control and treated groups for each strain (data not shown).


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

Vallanat B, Anderson SP, Brown-Borg HM, Ren H, Kersten S, Jonnalagadda S, Srinivasan R, Corton JC - BMC Genomics (2010)

PPARα-independent changes in triglyceride levels and fatty acid metabolism genes by heat shock. A. Serum levels of alkaline phosphatase, glucose and triglycerides 4 and 24 hrs after HS. B. Decreases in fatty acid metabolism genes by HS in wild-type and PPARα- mice. Genes called as significantly altered between control and HS groups were extracted from GSEA gene sets HSA03320_PPAR_SIGNALING_PATHWAY (wild-type mice) and HSA00071_FATTY_ACID_METABOLISM (PPARα- mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2823686&req=5

Figure 3: PPARα-independent changes in triglyceride levels and fatty acid metabolism genes by heat shock. A. Serum levels of alkaline phosphatase, glucose and triglycerides 4 and 24 hrs after HS. B. Decreases in fatty acid metabolism genes by HS in wild-type and PPARα- mice. Genes called as significantly altered between control and HS groups were extracted from GSEA gene sets HSA03320_PPAR_SIGNALING_PATHWAY (wild-type mice) and HSA00071_FATTY_ACID_METABOLISM (PPARα- mice).
Mentions: We examined the levels of a number of clinical chemistry markers including triglycerides in the blood from mice 4 or 24 hrs after HS. The levels of alkaline phosphatase were increased in all WY-treated wild-type mice but not PPARα- mice (Figure 3A), paralleling the increases in gene expression for alkaline phosphatase, liver/bone/kidney (Alpl) after exposure to WY and other PPC (data not shown). Consistent with PPARα agonists playing a role in glucose homeostasis [34,35], glucose levels were lower in wild-type but not PPARα- WY-treated mice at 4 and 24 hrs. HS also lowered glucose levels in wild-type but not PPARα- mice at 24 hrs. HS did not induce overt liver damage as measured by ALT levels; minor increases were observed by HS+WY treatment in wild-type but not PPARα- mice at 4 and 24 hrs that approached significance (data not shown). These results were consistent with a lack of pathological findings in the liver. In wild-type mice triglyceride levels were increased by HS and decreased by WY at 4 hrs with no change by both treatments. At 24 hrs, triglyceride levels were decreased by HS, WY or HS+WY in wild-type mice and by HS or HS+WY in PPARα- mice. Despite uniform increases in cholesterol biosynthetic genes after WY exposure that were reversed by WY+HS treatment (Additional File 8 and 9), no changes in circulating cholesterol were noted between control and treated groups for each strain (data not shown).

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

View Article: PubMed Central - HTML - PubMed

Affiliation: NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, USA. corton.chris@epa.gov

ABSTRACT

Background: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha and the HS response mediated by HSF1.

Results: Wild-type and PPARalpha- mice were exposed to HS, the PPARalpha 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 PPARalpha-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARalpha- mice that are known targets of PPARgamma co-activator-1 (PGC-1) family members. Pretreatment of PPARalpha- mice with WY increased expression of PGC-1beta 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- mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARalpha and HSF1, a number require both factors for HS responsiveness.

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

Show MeSH
Related in: MedlinePlus