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Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin

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ABSTRACT

Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine‐enzyme, which was described as to play bioactivities both in the intracellular and in the extracellular environment. However, while the functions of intracellular NAMPT (iNAMPT) are well known, much less is known on extracellular NAMPT (eNAMPT), also called visfatin or pre‐B cell colony‐enhancing factor. iNAMPT catalyzes the rate‐limiting step in the NAD+ biosynthesis pathway from nicotinamide. Its inhibition severely reduces intracellular NAD+ levels, achieving anti‐inflammatory and anti‐cancer effects. eNAMPT can be detected in the human circulation and in many extracellular environments. Studies show that eNAMPT can act as a growth factor, as an enzyme, and as a cytokine, but its true mechanism of secretion and its physiological functions are still debated. Increased levels of eNAMPT have been associated with different metabolic disorders and cancers. eNAMPT was demonstrated to modulate the pathways involved in the pathophysiology of obesity, diabetes, atherosclerosis, and cardiovascular events by regulating the oxidative stress response, apoptosis, and inflammation. In cancer, eNAMPT was shown to play a pivotal role in modulating cancer cell metabolism, in promoting epithelial‐to‐mesenchymal transition and in shaping the tumor microenvironment. In line with these functions, circulating eNAMPT levels are frequently increased in cancer patients. Given these pleiotropic roles of eNAMPT in human disease, this protein has attracted attention as a therapeutic target. In this narrative review, we will discuss recent evidence on eNAMPT‐driven signalling, highlighting the emerging pathophysiological roles of this protein in different disorders and the potential therapeutic opportunities linked to its targeting. © 2017 American Physiological Society. Compr Physiol 7:603‐621, 2017.

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Figure 1. Figure 1. Physiological activity of intracellular nicotinamide phosphoribosyltransferase (iNAMPT). iNAMPT catalyses the rate‐limiting reaction of the nicotinamide dinucleotide (NAD+) salvage pathway. NAMPT recycles nicotinamide (NAM), generating nicotinamide mononucleotide (NMN), which is the converted to NAD+ by the NMN adenylyltransferases (NMNAT1‐3). NAMPT expression is dependent on the circadian regulators CLOCK:BMAL1 in complex with SIRT1. iNAMPT modulates the activity of PARPs and of sirtuins located in the nucleus (SIRT1, SIRT6, and SIRT7), in the mitochondria (SIRT3, SIRT4, and SIRT5) and in the cytoplasm (SIRT1 and SIRT2). Some of the nucleotides produced by PARP, sirtuins, as well by other NAD+‐degrading enzymes (e.g., CD38) act as second messengers with calcium‐mobilizing effects. These include cADPR, ADPR, and NAADP.
Figure 2. Figure 2. Autocrine/paracrine effects of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT acts as a cytokine in a wide range of extracellular environments. Although its receptor has not been identified yet, eNAMPT may activate different intracellular cascades and then promote gene transcription. eNAMPT‐mediated cellular responses include the release of other cytokines and the activation of physiological/pathological intracellular pathways. NF‐κB: nuclear factor kappa‐light‐chain‐enhancer of activated B cells; IL: interleukin; ERK: extracellular signal‐regulated kinases; CD: cluster of differentiation; TNF: tumour necrosis factor; iNOS: inducible nitric oxide synthase; NO: nitric oxide; G‐CSF: granulocyte colony stimulating factor; MMP: matrix metalloproteinase; PI3K: phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; CCL: chemokine (C‐C motif) ligand; CCR: C‐C chemokine receptor; CXCL: chemokine (C‐X‐C motif) ligand; AMPK: 5' AMP‐activated protein kinase; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion molecule; SOD: superoxide dismutase; GSH: glutathione.


Figure 1. Physiological activity of intracellular nicotinamide phosphoribosyltransferase (iNAMPT). iNAMPT catalyses the rate‐limiting reaction of the nicotinamide dinucleotide (NAD+) salvage pathway. NAMPT recycles nicotinamide (NAM), generating nicotinamide mononucleotide (NMN), which is the converted to NAD+ by the NMN adenylyltransferases (NMNAT1‐3). NAMPT expression is dependent on the circadian regulators CLOCK:BMAL1 in complex with SIRT1. iNAMPT modulates the activity of PARPs and of sirtuins located in the nucleus (SIRT1, SIRT6, and SIRT7), in the mitochondria (SIRT3, SIRT4, and SIRT5) and in the cytoplasm (SIRT1 and SIRT2). Some of the nucleotides produced by PARP, sirtuins, as well by other NAD+‐degrading enzymes (e.g., CD38) act as second messengers with calcium‐mobilizing effects. These include cADPR, ADPR, and NAADP.


Figure 2. Autocrine/paracrine effects of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT acts as a cytokine in a wide range of extracellular environments. Although its receptor has not been identified yet, eNAMPT may activate different intracellular cascades and then promote gene transcription. eNAMPT‐mediated cellular responses include the release of other cytokines and the activation of physiological/pathological intracellular pathways. NF‐κB: nuclear factor kappa‐light‐chain‐enhancer of activated B cells; IL: interleukin; ERK: extracellular signal‐regulated kinases; CD: cluster of differentiation; TNF: tumour necrosis factor; iNOS: inducible nitric oxide synthase; NO: nitric oxide; G‐CSF: granulocyte colony stimulating factor; MMP: matrix metalloproteinase; PI3K: phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; CCL: chemokine (C‐C motif) ligand; CCR: C‐C chemokine receptor; CXCL: chemokine (C‐X‐C motif) ligand; AMPK: 5' AMP‐activated protein kinase; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion molecule; SOD: superoxide dismutase; GSH: glutathione.
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Teaching Material

Carbone F, Liberale L, Bonaventura A, Vecchiè A, Casula M, Cea M, Monacelli F, Caffa I, Bruzzone S, Montecucco F, Nencioni A. Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin. Compr Physiol 2017, 7: 603-621. doi: 10.1002/cphy.c160029

Didactic Synopsis

Major Teaching Points:

              Nicotinamide phosphoribosiltransferase (NAMPT), also known as visfatin, has functions both as an intracellular enzyme (iNAMPT; mediating the synthesis of nicotinamide mononucleotide -NAD+- from nicotinamide) and as a soluble factor secreted into the extracellular space (extracellular NAMPT, eNAMPT).

              eNAMPT has pro-inflammatory, pro-chemotactic, pro-angiogenic and insulin-like effects.

              NAMPT is frequently overexpressed by solid and hematologic malignancies.

              iNAMPT supports cancer cell metabolism and DNA repair (particularly in tumors with defects in their homologous recombination).

              eNAMPT promotes the acquisition of a mesenchymal phenotype in epithelial cells (facilitating metastasis) and of a protumorigenic phenotype in tumor-associated macrophages.

              Inhibitors of NAMPT enzymatic activity hold promise as cancer therapeutics and as anti-inflammatory drugs and so do neutralizing antibodies for eNAMPT.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching Points: intracellular NAMPT (iNAMPT) performs the synthesis of NAD+ starting from nicotinamide (NAM), which is produced intracellularly by many enzymes that actively degrade NAD+ itself during their enzymatic reactions. Such enzymes include the NAD+-dependent deacetylases, sirtuins, the DNA repair enzyme, PARP, as well as CD38. Some of the nucleotides produced by these NAD+-degrading enzymes act as second messengers with calcium-mobilizing effects.

Figure 2. Teaching Points: Once secreted into the extracellular space, extracellular NAMPT (eNAMPT) exerts cytokine-like functions, some of which are seemingly unrelated from its enzymatic activity. These include i) pro-inflammatory effects on immune cells, ii) the ability to stimulate endothelial cells, promoting angiogenesis, ii) the promotion of cardiac and neuronal cell survival, as well as iv) the ability to stimulate the so-named epithelial-to-mesenchymal transition and the secretion of pro-inflammatory and pro-angiogenic factors in cancer cells.

 

 


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How to Cite

Federico Carbone, Luca Liberale, Aldo Bonaventura, Alessandra Vecchiè, Matteo Casula, Michele Cea, Fiammetta Monacelli, Irene Caffa, Santina Bruzzone, Fabrizio Montecucco, Alessio Nencioni. Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin. Compr Physiol 2017, 7: 603-621. doi: 10.1002/cphy.c160029