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Author:
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Pedraza González, Neus; Rosell, Meritxell; Villarroya, Joan; Iglesias, Roser; Gonzalez, Frank J.; Solanes, Gemma; Villarroya, Francesc
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Notes:
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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.
We thank Drs. S. Green, P. Grimaldi, R. Evans, and L. Fajas for kindly supplying expression vectors and Dr. Chandraratna for AGN 194204. Address all correspondence and requests for reprints to: Dr. G. Solanes, Departament de Bioquı´mica i Biologia Molecular, Universitat de Barcelona, Avda Diagonal 645, E-08028 Barcelona, Spain. E mail: gsolanes@ub.edu. This work was supported by Grants SAF2002-03648 and SAF2005- 01722 from Ministerio de Educacio´n y Ciencia and Grant C03/08 from Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain. Disclosure of potential conflicts of interest: N.P., M.R., J.V., R.I., F.J.G., G.S., and F.V. have nothing to declare |
