Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease

Gariani, Karim; Ryu, Dongryeol; Menzies, Keir J.; Yi, Hyon‐Seung; Stein, Sokrates; Zhang, Hongbo; Perino, Alessia; Lemos, Vera; Katsyuba, Elena; Jha, Pooja; Vijgen, Sandrine Elisabeth; Rubbia‐Brandt, Laura; Kim, Yong Kyung; Kim, Jung Tae; Kim, Koon Soon; Shong, Minho; Schoonjans, Kristina; Auwerx, Johan

doi:10.1016/j.jhep.2016.08.024

Cited by 120 publications

(113 citation statements)

References 56 publications

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“…Raising NAD + levels back to those of young or lean mice has been particularly effective at preventing and treating obesity, alcoholic steatohepatitis and NASH, while improving glucose homeostasis and mitochondrial dysfunction. Approaches that have worked well in rodents include the inhibition of NAD + consuming enzymes such as PARPs (Bai et al, 2011; Gariani et al, 2017) and CD38 (Barbosa et al, 2007), the inhibition of nicotinamide N-methyltransferase (Nnmt) (Kraus et al, 2014) and supplementation with NAD + precursors, NR (Canto et al, 2012) or NMN (Yoshino et al, 2011). NAD boosting appears to not only improve the health of the liver, but also increase its capacity for regeneration and protect it against hepatotoxicity.…”

Section: Effects Of Nad+ Boosters On Physiology and Health In Mouse Mmentioning

confidence: 99%

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

2018

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Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD-sensing enzymes, NAD controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

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Section: Effects Of Nad+ Boosters On Physiology and Health In Mouse Mmentioning

confidence: 99%

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

2018

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“…Development of pharmacological pan-PARP [88] inhibitors have opened new avenues for targeting NAD + consuming enzymes. As expected, PARP inhibitors have been shown to elevate NAD + levels in multiple tissues such as muscle and liver [81], [96], [97], but adipose tissue has not been investigated in these studies. Furthermore, there are no human studies in which the effect of PARP inhibitor treatment on tissue NAD + levels has been investigated.…”

Section: The Maintenance Of Nad+ Homeostasis In Adipose Tissuementioning

confidence: 83%

Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

et al. 2017

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Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD+/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD+ homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD+ pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.

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“…PARP inhibitor olaparib improved hepatic fatty acid oxidation and NAFLD induced by HFHS-diet [18]. Pharmacological inhibition of PARP or genetic deletion of PARP1 can restored the hepatic NAD + content and increased SIRT1 activation, which decreased hepatic TG accumulation in both alcoholic and nonalcoholic steatohepatitis (ASH/NASH) [25].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PARP Activity Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice

Huang¹,

Zhang²,

Chen³

et al. 2017

Preprint

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Abstract:The specific role of nicotinamide adenine dinucleotide (NAD) in hepatic triglyceride (TG) accumulation in alcoholic fatty liver disease (AFLD) were unclear.Poly ADP ribose polymerase (PARP) is a NAD-consuming enzyme and its specific role in the pathogenesis of AFLD is still elusive. In current investigation, we found that chronic alcohol exposure enhanced hepatic PARP expression and activity and lowered hepatic NAD

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Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease

Cited by 120 publications

References 56 publications

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

Inhibition of PARP Activity Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice

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