title: Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western and non-Western countries, but its pathogenesis is not fully understood.
  
  
  OBJECTIVE
  Based on the role of nicotinamide phosphoribosyltransferase (NAMPT) in fat and glucose metabolism and cell survival, we hypothesized a role for NAMPT/visfatin in the pathogenesis of NAFLD-related disease.
  
  
  METHODS
  We conducted clinical studies at a referral medical center in well-characterized NAFLD patients (n = 58) and healthy controls (n = 27). In addition we performed experimental in vitro studies in hepatocytes.
  
  
  METHODS
  We examined 1) the hepatic and systemic expression of NAMPT/visfatin in patients with NAFLD and control subjects, 2) the hepatic regulation of NAMPT/visfatin, and 3) the effect of NAMPT/visfatin on hepatocyte apoptosis.
  
  
  RESULTS
  Our main findings were as follows. 1) Patients with NAFLD had decreased NAMPT/visfatin expression both systemically in serum and within the hepatic tissue, with no difference between simple steatosis and nonalcoholic steatohepatitis. 2) By studying the hepatic regulation of NAMPT/visfatin in wild-type and peroxisome proliferators-activated receptor (PPAR)alpha(-/-) mice as well as in hepatocytes, we showed that PPARalpha activation and glucose may be involved in the down-regulation of hepatic NAMPT/visfatin expression in NAFLD. 4) Within the liver, NAMPT/visfatin was located to hepatocytes, and our in vitro studies showed that NAMPT/visfatin exerts antiapoptotic effects in these cells, involving enzymatic synthesis of nicotinamide adenine dinucleotide.
  
  
  CONCLUSIONS
  Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital, N-0027 Oslo, Norway. tuvad@rr-research.no
authors.forename: Tuva B
authors.initials: TB
authors.lastname: Dahl
authors.forename: John Willy
authors.initials: JW
authors.lastname: Haukeland
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.forename: Ivar P
authors.initials: IP
authors.lastname: Gladhaug
authors.forename: Jan K
authors.initials: JK
authors.lastname: Damås
authors.forename: Terese
authors.initials: T
authors.lastname: Haaland
authors.forename: Else Marit
authors.initials: EM
authors.lastname: Løberg
authors.forename: Borghild
authors.initials: B
authors.lastname: Arntsen
authors.forename: Kåre
authors.initials: K
authors.lastname: Birkeland
authors.forename: Kristian
authors.initials: K
authors.lastname: Bjøro
authors.forename: Stine M
authors.initials: SM
authors.lastname: Ulven
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Konopski
authors.forename: Hilde I
authors.initials: HI
authors.lastname: Nebb
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000502:physiology*; D047493:PPAR alpha / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D047493:PPAR alpha; D034741:RNA, Small Interfering; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D005947:Glucose