Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.

Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC.

Palmitate significantly decreased viability (29±8.8%) of INS-1E β-cells compared to controls after 24h. Stimulation with oleate showed no effect on viability but the combination of oleate and palmitate improved viability compared to palmitate treated cells (55±9.3%) or controls (26±5.3%). The number of apoptotic cells was increased 2-fold after 24h incubation with palmitate compared to controls. Again, oleate showed no effect but in combination ameliorated the effect of palmitate to control level. Phosphorylation of eIF2α was increased after 6 and 24h incubation with palmitate. In contrast, oleate had no effect and in combination prevented phosphorylation of eIF2α. Increased Xbp1 splicing was visible already 6h after palmitate treatment and remained elevated at 24h. The combination with oleate abolished Xbp1 splicing. Interestingly, mRNA expression of the chaperones Bip, Pdi, Calnexin and Grp94 was not altered by FFA treatment. Only the proapoptotic transcription factor Chop was significantly enhanced by palmitate incubation. In accordance with sustained cell survival the combination as well as oleate alone, did not result in increased Chop levels compared to controls. In summary, we showed that oleate protects INS-1E β-cells from palmitate-induced apoptosis by the suppression of ER stress which was independent of chaperone activation.

Aims/HypothesisObesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) and its enzymatic product Nicotinamide mononucleotide (NMN), which has been associated with obesity and type 2 diabetes mellitus (T2DM) directly influence beta-cell survival and function.MethodsThe effect of Nampt and NMN on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product NMN on insulin secretion were assessed by glucose stimulated insulin secretion in human islets.ResultsWhile stimulation of beta-cells with the cytokines IL-1β, TNFα and IFN-γ or palmitate significantly decreased viability, Nampt and NMN showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines). At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1 h incubation of human islets.Conclusion/InterpretationNampt and NMN neither influenced beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion.