Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease

J Clin Endocrinol Metab. 2010 Jun;95(6):3039-47. doi: 10.1210/jc.2009-2148. Epub 2010 Apr 14.


Context: 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.

Design and setting: 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.

Main outcome measures: 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.

Conclusion: Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • Cells, Cultured
  • Down-Regulation
  • Fatty Liver / enzymology*
  • Fatty Liver / pathology
  • Female
  • Glucose / pharmacology
  • Hepatocytes / physiology*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Male
  • Mice
  • Middle Aged
  • Mitochondria, Liver / metabolism
  • NAD / metabolism
  • Nicotinamide Phosphoribosyltransferase / physiology*
  • PPAR alpha / metabolism
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection


  • Hypoglycemic Agents
  • Insulin
  • PPAR alpha
  • RNA, Small Interfering
  • NAD
  • Nicotinamide Phosphoribosyltransferase
  • Glucose