Extracellular nicotinamide phosphoribosyltransferase: role in disease pathophysiology and as a biomarker

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) plays a central role in mammalian cell metabolism by contributing to nicotinamide adenine dinucleotide biosynthesis. However, NAMPT activity is not limited to the intracellular compartment, as once secreted, the protein accomplishes diverse functions in the extracellular space. Extracellular NAMPT (eNAMPT, also called visfatin or pre-B-cell colony enhancing factor) has been shown to possess adipocytokine, pro-inflammatory, and pro-angiogenic activities. Numerous studies have reported the association between elevated levels of circulating eNAMPT and various inflammatory and metabolic disorders such as obesity, diabetes, atherosclerosis, arthritis, inflammatory bowel disease, lung injury and cancer. In this review, we summarize the current state of knowledge on eNAMPT biology, proposed roles in disease pathogenesis, and its potential as a disease biomarker. We also briefly discuss the emerging therapeutic approaches for eNAMPT inhibition.

In vitro effect of visfatin on endocrine functions of the porcine corpus luteum

“…Visfatin may affect target cells in two ways: it may bind cell surface receptors, such as earlier mentioned TLR4 and CCR5, and activate intracellular signalling pathways, and it may also act as an enzyme, including as an extracellular ectoenzyme 17 . Visfatin/NAMPT is an enzyme involved in the biosynthesis of NAD+, a crucial cofactor in cellular redox reactions.…”

“…Visfatin may activate the insulin receptor (INSR) by binding at a site other than insulin (INS) and thus act in target cells including pancreatic cells 14 , osteoblasts 15 , and renal mesangial cells 16 . More recently, several other putative visfatin cell surface receptors have been identified—for example, C–C chemokine receptor type 5 (CCR5) and Toll-like receptor 4 (TLR4)—with a dissociation constant (Kd) in the nanomolar range, indicating high affinity 17 .…”

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

“…The failure of the first NAMPT inhibitors in the clinic sparked efforts to optimize the use of these agents, which culminated in a second wave of NAMPT inhibitors (represented by OT-82 [49] and the dual NAMPT-PAK4 inhibitor KPT9274 [50]) being recently assessed in clinical trials. Several review articles discuss the medicinal chemistry aspects of the development of NAMPT inhibitors and also the emerging roles of NAMPT beyond being an enzyme that generates NAD + (since NAMPT also exists as an extracel-lular form mainly acting as a cytokine that was found to mediate multiple pro-oncogenic roles) [51][52][53][54][55]. We have also recently reviewed the preclinical and clinical aspects of NAD +lowering drugs, with a special focus on NAMPT inhibitors, including their downstream effects and their optimization strategies [8].…”