NAMPT inhibition reduces macrophage inflammation through the NAD+/ PARP1 pathway to attenuate liver ischemia-reperfusion injury

作者全名："Lu, Jiao; Wang, Menghao; Chen, Yucheng; Song, Hua; Wen, Diguang; Tu, Jianfei; Guo, Yuan; Liu, Zuojin"

作者地址："[Lu, Jiao; Wang, Menghao; Chen, Yucheng; Song, Hua; Wen, Diguang; Liu, Zuojin] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing 40010, Peoples R China; [Tu, Jianfei] Lishui Cent Hosp, Ctr Diagnost & Treatment Intervent, Lishui 323000, Zhejiang, Peoples R China; [Guo, Yuan] Chongqing Med Univ, Affiliated Hosp 2, Infect Dis Dept, Chongqing 40010, Peoples R China"

通信作者："Liu, ZJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing 40010, Peoples R China.; Guo, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Infect Dis Dept, Chongqing 40010, Peoples R China."

来源：CHEMICO-BIOLOGICAL INTERACTIONS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000974531000001

JCR分区：Q1

影响因子：5.1

年份：2023

卷号：369

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Liver ischemia-reperfusion injury; Liver macrophages; NAMPT; FK866; PARP1; Inflammation

摘要："Background: Liver ischemia-reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Previous studies have suggested that the inflammatory response participated in the liver damage during liver IRI. Nicotinamide phosphoribosyl transferase (NAMPT) is required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD+) levels, catalyzing the rate -limiting step in the NAD + salvage pathway. NAMPT is strongly upregulated during inflammation and constitutes an important mechanistic link between inflammatory, metabolic, and transcriptional pathways. The aim of our study was to investigate the role of NAMPT in liver IRI.Methods: We investigated the effect of pharmacological inhibition of NAMPT with FK866 in models of liver IRI. Liver damage was assessed by HE staining, serum ALT/AST, and TUNEL staining. To examine the mechanism, primary hepatocytes, liver macrophages and RAW264.7 cells were treated with or without NAMPT inhibitors before hypoxia-reoxygenation. Liver macrophages and RAW 264.7 cells activation in vitro was evaluated by western blotting, flow cytometry, and ELISA. Result: We found that NAMPT was upregulated in liver IRI. Treatment with the NAMPT inhibitor FK866 ameliorated liver IRI and suppressed inflammation in mice. Although NAMPT plays an important role both in hepatocytes and liver macrophages, we focused on the impact of NAMPT on liver macrophages. The mechanism revealed that FK866 potently inhibited NAMPT activity, as demonstrated by reduced liver NAD+ and intracel-lular NAD+, resulting in reduced abundance and activity of NAD +-dependent enzymes, including poly (ADP -ribose) polymerase 1 (PARP1), thus inhibiting macrophage M1 polarization by reducing CD86, iNOS, TNF-alpha, and interleukin (IL)-113. Taken together, our data suggested that NAMPT can regulate macrophage polarization through NAD+/PARP1 to ameliorate liver injury, and that FK866-mediated NAMPT blockade may be a thera-peutic approach in liver IRI."

基金机构：National Natural Science Foundation of China [82070678]; Chongqing Natural Science Foundation [cstc2019jcyj-zdxmX0027]

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (82070678) , and Chongqing Natural Science Foundation (cstc2019jcyj-zdxmX0027) ."