Hepatic NAD^+ deficiency as a therapeutic target for NAFLD in aging

作     者：WANG Pei MIAO Chao-yu 

作者机构：Department of PharmacologySecond Military Medical University 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2016年第30卷第10期

页      面：1055-1056页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：The project supported by National Natural Science Foundation of China(81373414,81130061,81473208,81422049) National 863 Plan Young Scientist Program of China(2015AA020943) Shanghai Qimingxing Project(14QA1404700) 

主　　题：NAD liver NAFLD NLRP3 

摘      要：OBJECTIVE Aging is an important risk factor of nonalcoholic fatty liver disease(NAFLD).Here,we investigated whether the deficiency of nicotinamide adenine dinucleotide(NAD+),a ubiquitous coenzyme,links aging with *** Hepatic NAD+concentration,together with the protein levels of nicotinamide phosphoribosyltransferase(NAMPT)and several other critical enzymes regulating NAD+biosynthesis,were compared between middle-aged and aged mice or *** influences of NAD+decline on the steatosis and steatohepatitis was evaluated in wild-type(WT)and H247A dominant-negative enzymatic-dead NAMPT transgenic mice(DN-NAMPT)under normal and high-fat diet(HFD).RESULTS Hepatic NAD+level decreased in aged mice and ***-controlled NAD+salvage,but not de novo biosynthesis pathway,was compromised in liver of elderly mice and *** normal chow,middle-age DN-NAMPT mice displayed systemic NAD+reduction,and had moderate NAFLD phenotypes,including lipid accumulation,enhanced oxidative stress,triggered inflammation and impaired insulin sensitivity in *** NAFLD phenotypes,especial y the pro-inflammatory factors release,Kupffer cell accumulation,monocytes infiltration,NLRP3 inflammasome pathway,and hepatic fibrosis(Masson’s staining and a-SMA staining),were further deteriorated under HFD *** administration of nicotinamide riboside,a natural NAD+precursor,completely corrected these NAFLD phenotypes induced by NAD+deficiency alone or HFD,whereas adenovirusmediated SIRT1 overexpression only partially rescued these *** These results provide the first evidence that aging-associated NAD+deficiency is a critical risk factor for NAFLD,and suggest that supplement of NAD+substrates may be a promising therapeutic strategy to prevent and treat NAFLD.