Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease.
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.
Dahl
Tuva B
TB
Research Institute for Internal Medicine, Oslo University Hospital, N-0027 Oslo, Norway. tuvad@rr-research.no
Haukeland
John Willy
JW
Yndestad
Arne
A
Ranheim
Trine
T
Gladhaug
Ivar P
IP
Damås
Jan K
JK
Haaland
Terese
T
Løberg
Else Marit
EM
Arntsen
Borghild
B
Birkeland
Kåre
K
Bjøro
Kristian
K
Ulven
Stine M
SM
Konopski
Zbigniew
Z
Nebb
Hilde I
HI
Aukrust
Pål
P
Halvorsen
Bente
B
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
D007004:Hypoglycemic Agents; D007328:Insulin; D047493:PPAR alpha; D034741:RNA, Small Interfering; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D005947:Glucose