title: Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.
abstract: Ageing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD.
  
  
  
  Hepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD(+) decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD).
  
  
  
  Hepatic NAD(+) level decreased in aged mice and humans. NAMPT-controlled NAD(+) salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given 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 liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD(+) precursor, completely corrected these NAFLD phenotypes induced by NAD(+) deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes.
  
  
  
  These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD.
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Can-Can
authors.initials: CC
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Hua
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Mao-Bing
authors.initials: MB
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Tian-Ying
authors.initials: TY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Miao
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009243:NAD / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D009243:NAD