NAMPT promotes hepatitis B virus replication and liver cancer cell proliferation through the regulation of aerobic glycolysis

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a critical rate-limiting enzyme involved in NAD synthesis that has been shown to contribute to the progression of liver cancer. However, the potential role and mechanism of NAMPT in hepatitis B virus (HBV)-associated liver cancer remain unclear. The present study assessed the expression of NAMPT in HBV-positive and-negative liver cancer cells, and investigated whether HBV-induced NAMPT expression is dependent on HBV X protein (HBx). In addition, the role of NAMPT in HBV replication and transcription, and in HBV-mediated liver cancer cell growth was explored. The effects of NAMPT on the glycolytic pathway were also evaluated. Reverse transcription-quantitative PCR and western blotting results revealed that NAMPT expression levels were significantly higher in HBV-positive liver cancer cells than in HBV-negative liver cancer cells, and this effect was HBx-dependent. Moreover, the activation of NAMPT was demonstrated to be required for HBV replication and transcription. The NAMPT inhibitor FK866 repressed cell survival and promoted cell death in HBV-expressing liver cancer cells, and these effects were attenuated by nicotinamide mononucleotide. Furthermore, the inhibition of NAMPT was associated with decreased glucose uptake, decreased lactate production and decreased ATP levels in HBV-expressing liver cancer cells, indicating that NAMPT may promote the aerobic glycolysis. Collectively, these findings reveal a positive feedback loop in which HBV enhances NAMPT expression and the activation of NAMPT promotes HBV replication and HBV-mediated malignant cell growth in liver cancer. The present study highlights the important role of NAMPT in the regulation of aerobic glycolysis in HBV-mediated liver cancer, and suggests that NAMPT may be a promising treatment target for patients with HBV-associated liver cancer.

Ca2+/Calmodulin-Dependent Protein Kinase II Inhibits Hepatitis B Virus Replication from cccDNA via AMPK Activation and AKT/mTOR Suppression

“…HBV has been shown to induce metabolic reprogramming to provide energy for HBV replication [ 6 , 7 , 8 ]. HBV infection increases glucose uptake, glycolytic metabolism, and lipid accumulation, which drive hepatic tissue damage resulting in the development of cirrhosis and HCC [ 9 , 10 , 11 ].…”

“…HBV infection increases glucose uptake, glycolytic metabolism, and lipid accumulation, which drive hepatic tissue damage resulting in the development of cirrhosis and HCC [ 9 , 10 , 11 ]. Although many metabolic proteins are involved in HBV replication [ 6 , 7 , 8 , 9 , 10 , 11 ], the underlying signaling pathway associated with metabolism during HBV replication has not yet been clearly determined. Evaluation of the metabolic signaling pathways associated with HBV replication showed that the AMPK activator metformin, which is used to treat patients with type 2 diabetes, suppressed the syntheses of HBe and HBs antigens and HBV replicative intermediate (RI) DNAs [ 12 ].…”

Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma

“…Importantly, stem cells are more resistant to apoptosis than parenchymal cells in the same tissue, and are able to grow because ATP production has shifted from oxidative phosphorylation to aerobic glycolysis. This metabolic shift appears to be mediated by HBx [ 63 ]. In CLD, the survival and proliferation of cells in cirrhotic nodules, which exist in a hypoxic environment, may result from the “stemness” characteristics conferred onto them by HBx ( Figure 1 ).…”

Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis

“…In addition, C-terminal-activating regions of LMP1 can promote GLUT1 transcription via the mTORC1/NF-κB signaling pathway ( Zhang et al., 2017 ). The hepatitis B virus core protein (HBc) and x protein (HBx) can increase key glycolytic enzymes and related genes NAMPT and NRF2 to enhance glycolysis ( Guo et al., 2021 ; Xie et al., 2017 ). Moreover, HCV severely impairs mitochondrial oxidative phosphorylation to promote HIF-1α expression and transcriptional activation, and its encoded proteins (NS5A and NS5B) can promote glycolytic enzymes’ activity to enhance glycolysis for viral replication ( Ramière et al., 2014 ; Ripoli et al., 2010 ; Wu et al., 2008 ).…”