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Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor a (PPARa)
Citation:
Hongzu, R., B. VALLANAT, H. Brown-Borg, R. Currie, AND C. CORTON. Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor a (PPARa). PPAR research. Hindawi Publishing Corporation, New York, NY, 1(doi 10 727194):1-14, (2011).
Impact/Purpose:
The study was carried out because no comprehensive information exists on the transcriptional changes of the genes involved in proteome maintenance altered by chemicals that activate PPARalpha.
Description:
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) is activated by a large number of xenobiotic and hypolipidemic compounds called peroxisome proliferator chemicals (PPC). One agonist of PPARa (WY-14,643) regulates responses in the mouse liver to chemical stress in part by altering expression of genes involved in proteome maintenance (PM) including protein chaperones in the heat shock protein (Hsp) family and proteasomal genes (Psm) involved in proteolysis. We hypothesized that other PPARa activators including diverse hypo lipidemic and xenobiotic compounds also regulate PM genes in the rat and mouse liver. We examined the expression of PM genes in rat and mouse liver after exposure to 7 different PPC using Affyrnetrix microarrays. In rats and mice 174 or 380 PM genes, respectively were regulated by at least one PPC. Many Hsp and Psm family members were commonly regulated by PPC in both rats and mice. The transcriptional changes were, for the most part dependent on PPARa, as most changes were not observed in similarly treated PPARa-null mice. In rats and mice, PM gene expression exhibited differences compared to typical direct targets of PPARa (e.g., Cyp4a family members); PM gene expression was usually delayed and in some cases, transient. Dose-response characterization of protein expression showed that Hsp86 and Hsp110 proteins were induced only at higher doses. These studies demonstrate that PPARa, activated by diverse PPC regulates the expression of a large number of genes involved in protein folding and degradation and support an expanded role for PPARa in the regulation of genes that protect the proteome
