A key role for Pre–B cell colony–enhancing factor in experimental hepatitis

Abstract

Pre-B cell colony-enhancing factor (PBEF), also known as nicotinamide phosphoribosyltransferase or visfatin, plays an important role in metabolic, inflammatory, and malignant diseases. Recent evidence suggests that blocking its enzymatic activity using a specific smallmolecule inhibitor (FK866) might be beneficial in acute experimental inflammation. We investigated the role of PBEF in human liver disease and experimental hepatitis. PBEF serum levels and hepatic expression were determined in patients with chronic liver diseases. These studies were followed by in vivo experiments using concanavalin A (ConA) and D-galactosamine/lipopolysaccharide (LPS) models of experimental hepatitis. PBEF was either overexpressed by hydrodynamic perfusion or inhibited by FK866. In vivo findings were corroborated studying inflammatory responses of lentivirally PBEF-silenced or control FL83B mouse hepatocytes. Here, we demonstrate that PBEF serum levels were increased in patients with chronic liver diseases irrespective of disease stage and etiology. In particular, we observed enhanced PBEF expression in hepatocytes. Liver-targeted overexpression of PBEF rendered mice more susceptible to ConA-and D-galactosamine/LPS-induced hepatitis compared with control animals. In contrast, inhibition of PBEF using FK866 protected mice from ConA-induced liver damage and apoptosis. Administration of FK866 resulted in depletion of liver nicotinamide adenine dinucleotide 1 levels and reduced proinflammatory cytokine expression. Additionally, FK866 protected mice in the D-galactosamine/LPS model of acute hepatitis. In vitro, PBEF-silenced mouse hepatocytes showed decreased responses after stimulation with LPS, lipoteichoic acid, and tumor necrosis factor a. In primary murine Kupffer cells, FK866 suppressed LPS-induced interleukin (IL)-6 production, whereas incubation with recombinant PBEF resulted in increased IL-6 release. Conclusion: Our data suggest that PBEF is of key importance in experimental hepatitis. Its specific inhibition might be considered a novel treatment option for inflammatory liver diseases. (HEPATOLOGY 2011; 54:675-686)

Nicotinamide Phosphoribosyltransferase Inhibitor Is a Novel Therapeutic Candidate in Murine Models of Inflammatory Lung Injury

“…FK-866 has been tested in spinal cord injury and experimental hepatitis in in vitro and in vivo models. FK-866 administration results in iNAD depletion and reduced proinflammatory cytokine expression (12,13). Although the extracellular proinflammatory effects of NAMPT/PBEF are well studied, little is known regarding how intracellular iNAMPT enzymatic activity contributes to ARDS pathogenesis.…”

The sensitivity of adipose tissue visfatin mRNA expression to lipopolysaccharide-induced endotoxemia is increased by ovariectomy in female rats

“…As a result, LPS-induced mRNA up-regulations of pro-inflammatory cytokines were attenuated by co-administration of visfatin antagonist (FK-866), suggesting that visfatin plays some roles in the enhanced inflammatory responses of WAT in OVX rats. It has been reported that, as noted above, visfatin induces the anorectic and febrile responses and plays a key role in experimental hepatitis in rodents [4,6]. We have previously reported that OVX female rats exhibited stronger anorectic and febrile responses than sham female rats [10].…”

“…It has been reported that visfatin plays roles in immune responses in both chronic and acute inflammatory conditions [1][2][3][4][5][6]. Visfatin transcription is regulated by interleukin (IL)-6, tumor necrosis factor (TNF), and glucocorticoids in adipose tissue, and it is also produced in neutrophils [5,18].…”

“…Visfatin is predominantly expressed in visceral fat, the liver, and leukocytes in both humans and rodents, and it plays roles as a cytokine-like factor in a variety of metabolic and immune responses [1][2][3]. In adipose tissue and the liver, visfatin has pro-inflammatory effects in various chronic diseases, such as type 2 diabetes, chronic hepatitis, and cardiovascular disease [1,4]. Although it has been reported that visfatin has insulin-mimetic effects that are mediated via its binding to the insulin receptor, this result has not been reproduced in other studies [3].…”

Plasma visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) concentration is not related to kidney function in elderly subjects

“…The interrelation between visfatin/NAMPT and inflammation is also supported by the observation that the synthesis of visfatin/NAMPT-like proinflammatory cytokines is upregulated in a wide range of inflammatory states such as inflammatory bowel diseases [27], arthritis [28], psoriasis [29], atherosclerosis [30], chronic obstructive pulmonary disease [31], and even pneumonia [32] or hepatitis [33]. In line with these findings, Carrero et al [34] demonstrated increased visfatin/NAMPT levels in stage 5 CKD patients with poor appetite, which is one of the signs associated with chronic inflammation.…”