Abstract
In the human hepatoma cell line HepG2, retinoic acid, clofibric acid, and bile acid treatment can only modestly increase hepatitis B virus (HBV) biosynthesis. Utilizing the human embryonic kidney cell line 293T, it was possible to demonstrate that the retinoid X receptor α (RXRα) plus its ligand can support viral biosynthesis independently of additional nuclear receptors. In addition, RXRα/peroxisome proliferator-activated receptor α (PPARα) and RXRα/farnesoid X receptor α (FXRα) heterodimeric nuclear receptors can also mediate ligand-dependent HBV transcription and replication when activated by clofibric acid and bile acid, respectively, independently of a requirement for the ligand-dependent activation of RXRα. These observations indicate that there are at least three possible modes of ligand-mediated activation of HBV transcription and replication existing within hepatocytes, suggesting that multiple independent mechanisms control viral production in the livers of infected individuals.
Highlights
In the human hepatoma cell line HepG2, retinoic acid, clofibric acid, and bile acid treatment can only modestly increase hepatitis B virus (HBV) biosynthesis
Treatment of HepG2 cells with retinoic acid, clofibric acid, and chenodeoxycholic acid modestly enhanced the level of HBV biosynthesis (Fig. 1A and B, lanes 2, 5, and 8), suggesting that these hepatoma cells express retinoid X receptor (RXR), peroxisome proliferator-activated receptor (PPAR), and farnesoid X receptor (FXR) that are capable of being activated in the presence of an exogenously added ligand
Exogenous expression of RXR␣, PPAR␣, and FXR␣ in the presence of added ligands resulted in a level of viral replication similar to that seen with ligand alone (Fig. 1B, lanes 4, 7, and 10)
Summary
In the human hepatoma cell line HepG2, retinoic acid, clofibric acid, and bile acid treatment can only modestly increase hepatitis B virus (HBV) biosynthesis. RXR␣/peroxisome proliferator-activated receptor ␣ (PPAR␣) and RXR␣/farnesoid X receptor ␣ (FXR␣) heterodimeric nuclear receptors can mediate ligand-dependent HBV transcription and replication when activated by clofibric acid and bile acid, respectively, independently of a requirement for the ligand-dependent activation of RXR␣ These observations indicate that there are at least three possible modes of ligand-mediated activation of HBV transcription and replication existing within hepatocytes, suggesting that multiple independent mechanisms control viral production in the livers of infected individuals. HBV transcription and replication can be supported by RXR␣/PPAR␣ and RXR␣/ FXR␣ in the absence of retinoids when these heterodimeric transcription factors are activated by peroxisome proliferators and bile acids, respectively It appears that the activation of both heterodimeric partners does not dramatically enhance the level of HBV transcription and replication compared to the level of viral biosynthesis observed with a single nuclear receptor ligand. If nuclear receptor antagonists are to be considered potential antiviral agents for the treatment of chronic HBV infections, it will be critical to distinguish between these different mechanisms of action so appropriate therapeutic modalities might be considered
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