Inhibition of NAD kinase elevates the hepatic NAD(+) pool and alleviates acetaminophen-induced acute liver injury in mice

作者全名："Liao, Cuiting; Zhang, Li; Jiang, Rong; Xu, Juanjuan; Tang, Jiarui; Hu, Kai; Jiang, Shifang; Li, Longhui; Yang, Yongqiang; Huang, Jiayi; Tang, Li; Li, Longjiang"

作者地址："[Liao, Cuiting; Zhang, Li; Jiang, Rong; Xu, Juanjuan; Tang, Jiarui; Hu, Kai; Jiang, Shifang; Yang, Yongqiang; Huang, Jiayi; Tang, Li; Li, Longjiang] Chongqing Med Univ, Basic Med Coll, Dept Pathophysiol, Chongqing 400016, Peoples R China; [Liao, Cuiting; Zhang, Li; Jiang, Rong; Xu, Juanjuan; Tang, Jiarui; Hu, Kai; Jiang, Shifang; Yang, Yongqiang; Huang, Jiayi; Tang, Li; Li, Longjiang] Chongqing Med Univ, Lab Stem Cell & Tissue Engn, Chongqing 400016, Peoples R China; [Li, Longhui] Univ Chinese Acad Sci, Chongqing Gen Hosp, Ctr Hlth Management, Chongqing 400000, Peoples R China; [Li, Longjiang] Yixueyuan Rd,Yuzhong Dist, Chongqing, Peoples R China"

通信作者："Li, LJ (通讯作者)，Yixueyuan Rd,Yuzhong Dist, Chongqing, Peoples R China."

来源：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000796598200011

JCR分区：Q2

影响因子：3.1

年份：2022

卷号：612

期号：　

开始页：70

结束页：76

文献类型：Article

关键词：Acetaminophen; Acute liver injury; Nicotinamide adenine dinucleotide kinase; Nicotinamide adenine dinucleotide; Oxidative stress

摘要："Acetaminophen (APAP) overdose induces acute liver injury (ALI), even acute liver failure (ALF). There is a significant unmet need to furtherly elucidate the mechanisms and find new therapeutic target. Recently, emerging evidence indicates that nicotinamide adenine dinucleotide (NAD(+)) plays a crucial role in APAPinduced ALI. Herein, we firstly investigated the protein expression of NAD kinase (NADK), as the rate limiting enzyme converting NAD(+& nbsp;)to nicotinamide adenine dinucleotide phosphate (NADP(+)), and found it was positively correlated with APAP-induced ALI in a dose-and time-dependent manner. Additionally, supplementation of N-acetylcysteine (NAC), known as an antidote of APAP, mitigated the ALI and downregulated the expression of NADK which was also in a dose-dependent manner. Moreover, pretreatment with methotrexate (MTX), the inhibitor of NADK, attenuated the levels of transaminases, alleviated morphological abnormalities, and improved oxidative stress triggered by APAP overdose, which was attributed to elevated hepatic NAD(+) pool. Subsequently, the increased NAD(+) upregulated the expression of Sirt1, SOD2 and attenuated DNA damage. Collectively, elevated expression of NADK is related to APAP-induced ALI, and inhibition of NADK alleviates the ALI through elevating liver NAD(+) level and improving antioxidant capacity. (C)& nbsp;2022 Elsevier Inc. All rights reserved."

基金机构：National Nat-ural Science Foundation of China [81871606]

基金资助正文：Funding This work was supported by the grants from the National Nat-ural Science Foundation of China (No. 81871606) .