PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / enzymology
  • Adipose Tissue, Brown / metabolism
  • Animals
  • Energy Metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism
  • NAD / metabolism
  • Oxidative Stress
  • Phenotype
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Small Interfering
  • NAD
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Sirt1 protein, mouse
  • Sirtuin 1