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

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2018 Apr 24

PMID 29684358

Citations 8

Authors

Li Q Zhang

Marianne Nsumu

Peixin Huang

Daniel P Heruth

Sean M Riordan

Katherine Shortt

Nini Zhang

Dmitry N Grigoryev

Ding-You Li

Craig A Friesen

Leon van Haandel

J Steven Leeder

Jody Olson

Shui Q Ye

Affiliations

Soon will be listed here.

Abstract

Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the United States. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild-type (Nampt), heterozygous knockout (Nampt), and overexpression (Nampt) mice were treated with overdose of acetaminophen, followed by histologic, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen-induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt mice, whereas the effects in Nampt mice were least severe relative to Nampt mice. Treatment of P7C3-A20, a small chemical molecule up-regulator of Nampt, ameliorated acetaminophen-induced mouse ALI over the reagent control. These findings support the fact that NAMPT protects against acetaminophen-induced ALI.

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References

Klaunig J, Goldblatt P, Hinton D, Lipsky M, Chacko J, Trump B . Mouse liver cell culture. I. Hepatocyte isolation. In Vitro. 1981; 17(10):913-25. DOI: 10.1007/BF02618288. View

Mazaleuskaya L, Sangkuhl K, Thorn C, FitzGerald G, Altman R, Klein T . PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015; 25(8):416-26. PMC: 4498995. DOI: 10.1097/FPC.0000000000000150. View

Cheranova D, Gibson M, Chaudhary S, Zhang L, Heruth D, Grigoryev D . RNA-seq analysis of transcriptomes in thrombin-treated and control human pulmonary microvascular endothelial cells. J Vis Exp. 2013; (72). PMC: 3601203. DOI: 10.3791/4393. View

Yuan L, Kaplowitz N . Mechanisms of drug-induced liver injury. Clin Liver Dis. 2013; 17(4):507-18, vii. PMC: 3793205. DOI: 10.1016/j.cld.2013.07.002. View

Cichoz-Lach H, Michalak A . Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014; 20(25):8082-91. PMC: 4081679. DOI: 10.3748/wjg.v20.i25.8082. View

Guarente L . Franklin H. Epstein Lecture: Sirtuins, aging, and medicine. N Engl J Med. 2011; 364(23):2235-44. DOI: 10.1056/NEJMra1100831. View

Lee W . Acute liver failure in the United States. Semin Liver Dis. 2003; 23(3):217-26. DOI: 10.1055/s-2003-42641. View

Hitomi J, Christofferson D, Ng A, Yao J, Degterev A, Xavier R . Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008; 135(7):1311-23. PMC: 2621059. DOI: 10.1016/j.cell.2008.10.044. View

Pieper A, Xie S, Capota E, Estill S, Zhong J, Long J . Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010; 142(1):39-51. PMC: 2930815. DOI: 10.1016/j.cell.2010.06.018. View

10.

Eguchi A, Wree A, Feldstein A . Biomarkers of liver cell death. J Hepatol. 2014; 60(5):1063-74. DOI: 10.1016/j.jhep.2013.12.026. View

11.

Nikiforov A, Kulikova V, Ziegler M . The human NAD metabolome: Functions, metabolism and compartmentalization. Crit Rev Biochem Mol Biol. 2015; 50(4):284-97. PMC: 4673589. DOI: 10.3109/10409238.2015.1028612. View

12.

Ramachandran A, McGill M, Xie Y, Ni H, Ding W, Jaeschke H . Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology. 2013; 58(6):2099-108. PMC: 3791212. DOI: 10.1002/hep.26547. View

13.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View

14.

Iorga A, Dara L, Kaplowitz N . Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis. Int J Mol Sci. 2017; 18(5). PMC: 5454931. DOI: 10.3390/ijms18051018. View

15.

Kaufman D, Kelly J, Rosenberg L, Anderson T, Mitchell A . Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002; 287(3):337-44. DOI: 10.1001/jama.287.3.337. View

16.

Ziegler M . New functions of a long-known molecule. Emerging roles of NAD in cellular signaling. Eur J Biochem. 2000; 267(6):1550-64. DOI: 10.1046/j.1432-1327.2000.01187.x. View

17.

Zhang L, Cheranova D, Gibson M, Ding S, Heruth D, Fang D . RNA-seq reveals novel transcriptome of genes and their isoforms in human pulmonary microvascular endothelial cells treated with thrombin. PLoS One. 2012; 7(2):e31229. PMC: 3281071. DOI: 10.1371/journal.pone.0031229. View

18.

McGill M, Jaeschke H . Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients. Expert Opin Drug Metab Toxicol. 2014; 10(7):1005-17. PMC: 4414250. DOI: 10.1517/17425255.2014.920823. View

19.

Chung R, Stravitz R, Fontana R, Schiodt F, Mehal W, Reddy K . Pathogenesis of liver injury in acute liver failure. Gastroenterology. 2012; 143(3):e1-e7. PMC: 3641754. DOI: 10.1053/j.gastro.2012.07.011. View

20.

Zhang M, Ying W . NAD Deficiency Is a Common Central Pathological Factor of a Number of Diseases and Aging: Mechanisms and Therapeutic Implications. Antioxid Redox Signal. 2018; 30(6):890-905. DOI: 10.1089/ars.2017.7445. View