PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation

By P. Bai, C. Cantó, Hughes Oudart, Attila Brunyánszki, Yana Cen, Charles Thomas, Hiroyasu Yamamoto, Aline Huber, B. Kiss, R. Houtkooper and 5 more. Cell Metabolism, 2011

812 citations recorded by the source corpus.

Summary 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, 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 not only could be useful in the management of metabolic diseases but also of cancer.

Subfields: Geriatrics and Gerontology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/3a93b1a1310d1d7c1a4b23eada1d8e1aca3aa795

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Citations in the corpus

The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling (2013, positive): “…PARP1 and PARP2 representing the main PARP activities in mammals—were classically described as DNA repair proteins (Gibson and Kraus, 2012; Schreiber et al., 2006), but recent studies have linked these proteins to metabolism (Asher et al., 2010; Bai et al., 2011a, 2011b; Erener et al., 2012).”
Sirt1 and the Mitochondria (2016, background): “PARP-1 knockout mice have a higher mitochondrial content, an increase in energy expenditure, and were protected against metabolic disease (Bai et al., 2011).”
CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism (2016, positive): “Furthermore, PARP1 has been proposed to be involved in NAD decline in tissues, and SIRT1 is an NAD-dependent deacetylase that plays a key role in age-related metabolic phenotypes (Bai et al., 2011; Bai and Cantó, 2012; Imai and Guarente, 2014).”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “Also, the pharmacological inhibition of PARP in vitro and in vivo increased SIRT1 activity (24).”
On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. (2012, background): “PARP-2 / mice also show metabolic effects (Bai et al. 2011a), including elevated energy expenditure, oxygen consumption, lipid oxidation associated with a leaner phenotype, protection against diet-induced obesity, and a tissue-specific mitochondrial metabolic phenotype (most evident in skeletal…”
NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “This further illustrates how PARP activity leads to SIRT1 inactivation, either by limiting NAD+ levels, in the case of PARP1 (Bai et al., 2011b), or by acting as a transcriptional repressor, in the case of PARP2 (Bai et al., 2011a).”
The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity (2012, positive): “Liver triglyceride measurement Liver triglycerides were measured from 20 mg of liver tissue using a variation of the Folch method, as described (Bai et al., 2011a).”
NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism (2018, background): “These effects were further confirmed in cultured cells with PARP1 or PARP2 silencing, but were attenuated by simultaneous knockdown of SIRT1 in PARP1- or PARP2-deficient cells (9), suggesting that enhanced mitochondrial function requires NAD-dependent SIRT1 activity in PARP-deficient cells.”
SIRT1 and other sirtuins in Metabolism (2013, result): “This finding is complementary to an earlier study showing that PARP-1 inhibition in mice increased NAD+ content and up-regulated SIRT1 [116].”
Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, positive): “The majority of NAD+ is salvaged from NAM, the product of CD38 and the PARPs (Magni et al., 1999, 2004) or from the various forms of niacin taken up in the diet, including NAM, NA, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) (Bogan and Brenner, 2008; Mills et al., 2016; Trammel”
Regulation of SIRT1 and Its Roles in Inflammation (2022, background): “found that in brown adipose and muscle tissues, PARP1 depletion or inhibition could increase SIRT1 activity in vivo and in vitro, respectively (63).”
Defective Mitophagy in XPA via PARP1 Hyperactivation and NAD+/SIRT1 Reduction (2014, background): “SIRT1 (Bai et al., 2011; Lagouge et al., 2006), we measured the expression level and activity of these two proteins.”
Sirtuins as regulators of metabolism and healthspan (2012, background): “It is tempting to speculate that such conditions also activate the PARP enzymes, a family of major NAD + consumers, thereby depleting NAD + levels and inhibiting SIRT1 activit”
NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, neutral): “In contrast, pharmacological or genetic inhibitionofother keyNAD+-consumingenzymes,suchasPARP1/2and CD38, is sufficient to confer beneficial effects that have been attributed to increased tissue NAD+ availability (Bai et al., 2011a, 2011b; Camacho-Pereira et al., 2016).”