AIM To assess the effects of hepatitis B virus (HBV) on the expression of host alpha-1,2-mannosidases and determine the underlying mechanisms. METHODS We measured the expression levels of MAN1A1, MAN1A2, MAN1B1, and MAN1C1 in cell lines HepG2.2.15, HepN10, HepAD38 and HepG2 by Western blot. Viral antigens (HBsAg and HBeAg) in the culture medium were measured using the chemiluminescence method. HBV DNA quantification assays were performed using a commercial real-time PCR kit. Protein levels of human liver tissue alpha-1,2-mannosidases were also evaluated by Western blot. Plasmids containing seven individual viral genes of HBV (PTT22-HBx, PTT22-HBs, PTT22-preS2, PTT22-preS1, PTT22-HBc, PTT22-HBe, and PTT22-HBp) or control plasmids (PTT22-vector) were transfected into HepG2 cells. MK886 (PPAR alpha) and GW9662 (PPAR.) inhibitors were used to explore the effects of HBV on a-1,2-mannosidase expression after the PPARa and PPAR. pathways were blocked. RESULTS We showed that the expression of alpha-1,2-mannosidases was higher in stably transfected HBV cells than in controls. The expression levels of alpha-1,2-mannosidase were higher in AD38 cells than those in ND10 cells, which were in turn greater than those in G2.2.15 cells, and positively correlated with the expression of HBsAg in all the cell lines. Levels of alpha-1,2-mannosidase in non-tumorous liver tissues of HBV-related HCC patients were also higher than in the tissues from non-HBV-related HCC patients. Moreover, transfecting HepG2 cells with a component of the HBV viral envelope also increased the expression of alpha-1,2-mannosidases. However, this envelope protein component could not induce MAN1C1 expression in the presence of a PPAR alpha inhibitor, MK886. We also found that MK886 did not affect the expression of MAN1C1 in AD38 cells without tetracycline in the culture medium. This phenomenon was not observed in the case of GW9662. CONCLUSION Our results indicate that HBV increases the expression of alpha-mannosidases both in vitro and in vivo via activation of the PPAR alpha pathway by its envelope protein.