Developmental and Tissue-Specific Involvement of Peroxisome Proliferator-Activated Receptor-α in the Control of Mouse Uncoupling Protein-3 Gene Expression
Gonzalez, Frank J.
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Uncoupling protein-3 (UCP3) is a member of the mitochondrial carrier family expressed preferentially in skeletal muscle and heart. It appears to be involved in metabolic handling of fatty acids in a way that minimizes excessive production of reactive oxygen species. Fatty acids are powerful regulators of UCP3 gene transcription. We have found that the role of peroxisome proliferator-activated receptor- (PPAR ) on the control of UCP3 gene expression depends on the tissue and developmental stage. In adults, UCP3 mRNA expression is unaltered in skeletal muscle from PPAR -null mice both in basal conditions and under the stimulus of starvation. In contrast, UCP3mRNAis down-regulated in adult heart both in fed and fasted PPAR -null mice. This occurs despite the increased levels of free fatty acids caused by fasting in PPAR - null mice. In neonates, PPAR -null mice show impaired UCP3 mRNA expression in skeletal muscle in response to milk intake, and this is not a result of reduced free fatty acid levels. The murineUCP3promoter is activated by fatty acids through either PPAR or PPAR but not by PPAR or retinoid X receptor alone. PPAR -dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPAR . However, among transcripts from other PPAR and PPAR target genes, only those acutely induced by milk intake in wild-type neonates were altered in muscle or heart from PPAR -null neonates. Thus, PPAR -dependent regulation is required for appropriate gene regulation of UCP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart.