内脏素(Visfatin/PBEF1/Nampt)和代谢综合症

Pre-B-cell colony-enhancing factor (PBEF)是美国Amgen公司的Samal博士在1994年首次报告的一个从人外周血液淋巴细胞基因库克隆的细胞因子， 有473个氨基酸残基，分子量在52KD。当初人们对他的生物学意义主要集中在炎症、创伤、休克和免疫调控等方面的研究。其中2005年美国约翰豪普金斯大学的华裔学者 研究发现PBEF还是一个非常可靠的反映急性肺损伤的生物标示物，并在急性肺损伤患者体内发现PBEF的点突变现象。 2005年日本学者研究发现PBEF还是内脏白色脂肪细胞合成分泌的一种脂肪因子。在细胞培养的实验研究中发现PBEF具有类似胰岛素样生物学效应，静脉给予PBEF可以降低小鼠血糖水平。因而，称为“内脏素“ (visfatin)。这一研究结果被发表在科学杂志。尽管以后许多学者难以重复这一实验结果，人们还是对内脏素在代谢综合征生物学意义， 特别是检测生物标示物意义还是肯定的。
内脏素的检测可以通过酶联免疫、蛋白质印迹试剂盒。可以检测血清或血浆的样本。检测时样本可能需要稀释1-2倍。

Intracellular nicotinamide phosphoribosyltransferase (iNampt) is an essential enzyme in the NAD biosynthetic pathway. An extracellular form of this protein (eNampt) has been reported to act as a cytokine named PBEF or an insulin-mimetic hormone named visfatin, but its physiological relevance remains controversial. Here we show that eNampt does not exert insulin-mimetic effects in vitro or in vivo but rather exhibits robust NAD biosynthetic activity. Haplodeficiency and chemical inhibition of Nampt cause defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets in vivo and in vitro. These defects are corrected by administration of nicotinamide mononucleotide (NMN), a product of the Nampt reaction. A high concentration of NMN is present in mouse plasma, and plasma eNampt and NMN levels are reduced in Nampt heterozygous females. Our results demonstrate that Nampt-mediated systemic NAD biosynthesis is critical for beta cell function, suggesting a vital framework for the regulation of glucose homeostasis.

Revollo JR, et al. Cell Metab. 2007 Nov;6(5):363-75.

PURPOSE OF REVIEW: Nicotinamide adenine dinucleotide (NAD) is a classic coenzyme in cellular redox reactions. Recently, NAD biochemistry has also been implicated in a broader range of biological functions in mammals, but the regulation of NAD biosynthesis has been poorly investigated. Recent progress in the field of NAD biochemistry has fueled new interest in the NAD biosynthetic pathways from its precursors and their physiological roles in metabolism. This review summarizes the latest knowledge on the NAD biosynthetic pathways and focuses on one of the key NAD biosynthetic enzymes, namely, nicotinamide phosphoribosyltransferase. RECENT FINDINGS: Mammals predominantly use nicotinamide rather than nicotinic acid as a precursor for NAD biosynthesis. Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that converts nicotinamide to nicotinamide mononucleotide in the NAD biosynthetic pathway from nicotinamide in mammals. The same protein has also been identified as a cytokine (pre-B-cell colony-enhancing factor or PBEF) or an insulin-mimetic hormone (visfatin). SUMMARY: We propose that the presumed multiple effects of Nampt/PBEF/visfatin may be entirely explained by its role as an intra and extracellular NAD biosynthetic enzyme. We also propose a new model of Namp/PBEF/visfatin-mediated systemic NAD biosynthesis and its possible physiological significance. Our model provides an important insight into developing preventive/therapeutic interventions for metabolic complications, such as obesity and diabetes.

Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor

A novel gene coding for the pre-B-cell colony-enhancing factor (PBEF) has been isolated from a human peripheral blood lymphocyte cDNA library. The expression of this gene is induced by pokeweed mitogen and superinduced by cycloheximide. It is also induced in the T-lymphoblastoid cell line HUT 78 after phorbol ester (phorbol myristate acetate) treatment. The predominant mRNA for PBEF is approximately 2.4 kb long and codes for a 52-kDa secreted protein. The 3' untranslated region of the mRNA has multiple TATT motifs, usually found in cytokine and oncogene messages. The PBEF gene is mainly transcribed in human bone marrow, liver tissue, and muscle. We have expressed PBEF in COS 7 and PA317 cells and have tested the biological activities of the conditioned medium as well as the antibody-purified protein in different in vitro assays. PBEF itself had no activity but synergized the pre-B-cell colony formation activity of stem cell factor and interleukin 7. In the presence of PBEF, the number of pre-B-cell colonies was increased by at least 70% above the amount stimulated by stem cell factor plus interleukin 7. No effect of PBEF was found with cells of myeloid or erythroid lineages. These data define PBEF as a novel cytokine which acts on early B-lineage precursor cells.

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