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Cell Metab. 2011 Apr 6;13(4):461-468. doi: 10.1016/j.cmet.2011.03.004.

PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.

Author information

1
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France; Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary.
2
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
3
CEPE, CNRS UPR9010, Strasbourg, France.
4
Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary.
5
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
6
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France.
7
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

Abstract

SIRT1 regulates energy homeostasis by controlling the acetylation status and activity of a number of enzymes and transcriptional regulators. The fact that NAD(+) levels control SIRT1 activity confers a hypothetical basis for the design of new strategies to activate SIRT1 by increasing NAD(+) availability. Here we show that the deletion of the poly(ADP-ribose) polymerase-1 (PARP-1) gene, encoding a major NAD(+)-consuming enzyme, increases NAD(+) content and SIRT1 activity in brown adipose tissue and muscle. PARP-1(-/-) mice phenocopied many aspects of SIRT1 activation, such as a higher mitochondrial content, increased energy expenditure, and protection against metabolic disease. Also, the pharmacologic inhibition of PARP in vitro and in vivo increased NAD(+) content and SIRT1 activity and enhanced oxidative metabolism. These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer.

PMID:
21459330
PMCID:
PMC3086520
DOI:
10.1016/j.cmet.2011.03.004
[Indexed for MEDLINE]
Free PMC Article

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