Multiple steps of the life cycle of hepatitis B virus (HBV) are known to be coupled to hepatic metabolism. However, the details of involvement of the hepatic metabolic milieu in HBV
infection remain incompletely understood. Hepatic lipid metabolism is controlled by a complicated
transcription factor network centered on
retinoid X receptor alpha (RXRα). Here, we report that RXRα negatively regulates HBV
infection at an early stage in cell cultures. The RXR-specific agonist
bexarotene inhibits HBV in HepG2 cells expressing the
sodium taurocholate cotransporting polypeptide (NTCP) (HepG2-NTCP), HepaRG cells, and primary Tupaia hepatocytes (PTHs); reducing RXRα expression significantly enhanced HBV
infection in the cells. Transcriptome sequencing (
RNA-seq) analysis of HepG2-NTCP cells with a disrupted RXRα gene revealed that reduced gene expression in
arachidonic acid (AA)/
eicosanoid biosynthesis pathways, including the AA synthases
phospholipase A2 group IIA (PLA2G2A), is associated with increased HBV
infection. Moreover, exogenous treatment of AA inhibits HBV
infection in HepG2-NTCP cells. These data demonstrate that RXRα is an important cellular factor in modulating HBV
infection and implicate the participation of AA/
eicosanoid biosynthesis pathways in the regulation of HBV
infection.IMPORTANCE Understanding how HBV
infection is connected with hepatic lipid metabolism may provide new insights into
virus infection and its pathogenesis. By a series of genetic studies in combination with transcriptome analysis and pharmacological assays, we here investigated the role of cellular
retinoid X receptor alpha (RXRα), a crucial
transcription factor for controlling hepatic lipid metabolism, in de novo HBV
infection in cell cultures. We found that silencing of RXRα resulted in elevated HBV covalently closed
circular DNA (cccDNA) formation and
viral antigen production, while activation of RXRα reduced HBV
infection efficiency. Our results also showed that silencing
phospholipase A2 group IIA (PLA2G2A), a key
enzyme of
arachidonic acid (AA) synthases, enhanced HBV
infection efficiency in HepG2-NTCP cells and that exogenous AA treatment reduced de novo HBV
infection in the cells. These findings unveil RXRα as an important cellular factor in modulating HBV
infection and may point to a new strategy for host-targeted
therapies against HBV.