PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.

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.

journal_name

Cell Metab

journal_title

Cell metabolism

authors

Bai P,Cantó C,Oudart H,Brunyánszki A,Cen Y,Thomas C,Yamamoto H,Huber A,Kiss B,Houtkooper RH,Schoonjans K,Schreiber V,Sauve AA,Menissier-de Murcia J,Auwerx J

doi

10.1016/j.cmet.2011.03.004

subject

Has Abstract

pub_date

2011-04-06 00:00:00

pages

461-468

issue

4

eissn

1550-4131

issn

1932-7420

pii

S1550-4131(11)00091-X

journal_volume

13

pub_type

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