Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-Induced Acute Liver Injury in Mice

Zhang, Li Qin; Nsumu, Marianne; Huang, Peixin; Heruth, Daniel P.; Riordan, Sean M.; Shortt, Katherine; Zhang, Nini; Grigoryev, Dmitry N.; Li, Ding‐You; Friesen, Craig A.; Haandel, Leon van; Leeder, J. Steven; Olson, Jody C.; Ye, Shui Qing

doi:10.1016/j.ajpath.2018.04.004

Cited by 12 publications

(7 citation statements)

References 47 publications

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“…Sirtuin activators and their clinical applications are listed in Table 2. [124], Sands et al [125], Krueger et al [126], Venkatasubramanian et al [127] Liu et al [89] Voorhees et al [128], Tesla et al [129], Blaya et al [130], Zhang et al [131],Oku et al [132], Wang et al [133] Abbreviations: AD -Alzheimer's disease, ALS -amyotrophic lateral sclerosis NAD-boosting molecules constitute a newer class of STACs [134]. Since 2003, studies have shown that recycling NAD from nicotinamide by upregulating the NAD remediation pathway can mimic calorie restriction and extend the lifespan of yeast [135].…”

Section: Sirt1 Activators and Their Neuroprotective Effects In Pdmentioning

confidence: 99%

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

et al. 2020

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Silence information regulator 1 (SIRT1), a member of the sirtuin family, targets histones and many non-histone proteins and participates in various physiological functions. The enzymatic activity of SIRT1 is decreased in patients with Parkinson's disease (PD), which may reduce their ability to resist neuronal damage caused by various neurotoxins. As far as we know, SIRT1 can induce autophagy by regulating autophagy related proteins such as AMP-activated protein kinase, light chain 3, mammalian target of rapamycin, and forkhead transcription factor 1. Furthermore, SIRT1 can regulate mitochondrial function and inhibit oxidative stress mainly by maintaining peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in a deacetylated state and thus maintaining a constant level of PGC-1α. Other studies have demonstrated that SIRT1 may play a role in the pathophysiology of PD by regulating neuroinflammation. SIRT1 deacetylases nuclear factor-kappa B and thus reduces its transcriptional activity, inhibits inducible nitric oxide synthase expression, and decreases tumor necrosis factor-alpha and interleukin-6 levels. SIRT1 can also upregulate heat shock protein 70 by deacetylating heat shock factor 1 to increase the degradation of α-synuclein oligomers. Few studies have focused on the relationship between SIRT1 single nucleotide polymorphisms and PD risk, so this topic requires further research. Based on the neuroprotective effects of SIRT1 on PD, many in vitro and in vivo experiments have demonstrated that some SIRT1 activators, notably resveratrol, have potential neuroprotective effects against dopaminergic neuronal damage caused by various neurotoxins. Thus, SIRT1 plays a critical role in PD development and might be a potential target for PD therapy.

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Section: Sirt1 Activators and Their Neuroprotective Effects In Pdmentioning

confidence: 99%

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

et al. 2020

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“…We identified 9 NAD metabolism in our screen data (Supplementary Table 5). Additionally, data from our lab suggest overexpression of NAMPT, a gene involved in NAD salvage, is protective against APAP-induced hepatotoxicity in vivo 35 .…”

Section: Resultsmentioning

confidence: 86%

“…RNA-seq data from mice previously published by our lab (GSE110787) evaluating the effect of APAP overdose on RNA expression changes in the liver was 7 male 11 week old C57BL/6 mice, 4 saline treated control mice and 3 mice 24 h after 200 mg/kg APAP (Sigma cat. A7085, St. Louis, MO) exposure via intraperitoneal injection, underwent RNA-sequencing on an Illumina HiSeq 1500 35 . RNA was isolated from liver using the MirVana miRNA isolation kit (Thermo Fisher cat.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Regulatory Genes in APAP Induced Hepatocyte Toxicity by a Genome-Wide CRISPR-Cas9 Screen

Shortt

Heruth

Zhang

et al. 2019

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Acetaminophen (APAP) is a commonly used analgesic responsible for more than half of acute liver failure cases. Identification of previously unknown genetic risk factors would provide mechanistic insights and novel therapeutic targets for APAP-induced liver injury. This study used a genome-wide CRISPR-Cas9 screen to evaluate genes that are protective against, or cause susceptibility to, APAP-induced liver injury. HuH7 human hepatocellular carcinoma cells containing CRISPR-Cas9 gene knockouts were treated with 15 mM APAP for 30 minutes to 4 days. A gene expression profile was developed based on the 1) top screening hits, 2) overlap of expression data from APAP overdose studies, and 3) predicted affected biological pathways. We further demonstrated the implementation of intermediate time points for the identification of early and late response genes. This study illustrated the power of a genome-wide CRISPR-Cas9 screen to systematically identify novel genes involved in APAP-induced hepatotoxicity and to provide potential targets to develop novel therapeutic modalities.

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“…The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Science and Technology Bureau of Yuzhong District [2015- [16][17][18][19] and Basic Medical College Research Plan .…”

Section: Author Contributionsmentioning

confidence: 99%

Nicotinamide improves NAD⁺ levels to protect against acetaminophen-induced acute liver injury in mice

Zhang

Jiang

et al. 2021

Hum Exp Toxicol

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Acetaminophen (APAP) overdose causes acute liver injury (ALI). Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme, and NAD+ is oxidized type which synthesized from nicotinamide (NAM). The present study aimed to investigate the role of NAD+ in ALI and protective property of NAM. The mice were subjected to different doses APAP. After 8 hours, the serum activities of alaninetransaminase (ALT) and aspartate aminotransferase (AST), the hepatic NAD+ level and nicotinamide phosphoribosyltransferase (NAMPT) expression were determined. Then, the mice were pretreated with NAM (800 mg/kg), the hepatoprotective effects and the key antioxidative molecules were evaluated. Our findings indicated that APAP resulted in remarkable NAD+ depletion in a dose-dependent manner accompanied by NAMPT downregulation, and NAM pretreatment significantly elevated the NAD+ decline due to upregulation of NAMPT. Moreover, the downregulated Kelch-like ECH-associated protein-1 (Keap1), upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation activation after NAM administration were confirmed, which were in accordance with improved superoxide dismutase (SOD) and glutathione (GSH) levels. Finally, NAM dramatically exhibited hepatoprotective effects by reducing the liver index and necrotic area. This study has suggested that APAP impairs liver NAD+ level and NAM is able to improve hepatic NAD+ to activate antioxidant pathway against APAP-induced ALI.

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Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-Induced Acute Liver Injury in Mice

Cited by 12 publications

References 47 publications

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

Identification of Novel Regulatory Genes in APAP Induced Hepatocyte Toxicity by a Genome-Wide CRISPR-Cas9 Screen

Nicotinamide improves NAD⁺ levels to protect against acetaminophen-induced acute liver injury in mice

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Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-Induced Acute Liver Injury in Mice

Cited by 12 publications

References 47 publications

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

Identification of Novel Regulatory Genes in APAP Induced Hepatocyte Toxicity by a Genome-Wide CRISPR-Cas9 Screen

Nicotinamide improves NAD+ levels to protect against acetaminophen-induced acute liver injury in mice

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Nicotinamide improves NAD⁺ levels to protect against acetaminophen-induced acute liver injury in mice