Independent Activation of Hepatitis B Virus Biosynthesis by Retinoids, Peroxisome Proliferators, and Bile Acids

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 ␣ (RXR␣) plus its ligand can support viral biosynthesis independently of additional nuclear receptors. In addition, RXR␣/peroxisome proliferator-activated receptor ␣ (PPAR␣) and RXR␣/farnesoid X receptor ␣ (FXR␣) 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 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. Hepatitis B virus (HBV) infection is primarily restricted to hepatocytes in the liver. This restriction is believed to occur at two distinct levels (1). The receptor(s) involved in viral entry is presumably present only on hepatocytes and governs species specificity (2). In addition, viral biosynthesis is restricted in a tissueand cell-type-specific manner because HBV transcription is dependent on liver-enriched transcription factors (3, 4). A variety of nuclear receptors have been shown to regulate HBV pregenomic 3.5-kb RNA synthesis and hence viral replication (5-7). Three of these nuclear receptors, retinoid X receptor (RXR), peroxisome proliferator-activated receptor (PPAR), and farnesoid X receptor (FXR), are ligand-dependent transcription factors that are activated by retinoids, peroxisome proliferators, and bile acids, respectively (8, 9). Therefore, it is apparent that the ligands for these nuclear receptors might be critical determinants of viral biosynthesis under both normal and pathophysiological conditions within the livers of infected individuals (10, 11).As the ligand-activated heterodimeric nuclear receptors RXR␣/PPAR␣ and RXR␣/FXR␣ regulate HBV pregenomic RNA synthesis by the recruitment of coactivators, it was of interest to evaluate the relative contributions of the individual heterodimeric partners to the overall level of viral transcription and replication (5, 6, 12). Characterization of the relative roles of individual polypeptides in the transcriptional activity of various heterodimeric nuclear receptors has been evaluated (13-15). This approach indicated that one partner might play a dominant role in controlling promoter activity depending on the nuclear receptors involved (13-15). Therefore, it was of interest to evaluate the effects of retinoids, peroxisome proliferators, and bile acids, alone or in combination, on HBV transcription and replication.In the current study, it is demonstrated that retinoids can activate HBV biosynthesis utilizing both RXR␣-containing homodimers and heterodimers. Alternativ...

The Hepatitis B Virus Receptor

“…However, in an HBV transgenic model, FXR is involved in HBV biosynthesis only to a limited extent (Reese et al 2012). Other nuclear receptors are also capable of regulating HBV transcription and replication (Reese et al 2013). Most of these studies only reflect changes in HBV gene expression associated with a single viral replication step.…”

Interactions of Hepatitis B Virus Infection with Nonalcoholic Fatty Liver Disease: Possible Mechanisms and Clinical Impact

“…It can include the ubiquitous TFs (such as CCAAT/enhancer binding protein (C/EBP) [51] and cyclic AMP response element-binding protein (CREB) [52]), the hepatic enriched master TFs (such as the hepatic nuclear factor 3 (HNF3)/FoxA [53] and HNF4 [54]), and some orphan receptors or coactivator (such as farnesoid X receptor (FXR) [55], retinoid X receptor (RXR) [56], peroxisome proliferator-activated receptor (PPAR) a [56,57], and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) [58]). Most of the above TFs, such as the HNF4a, FXR, RXR, and PPARa, play key roles in maintaining the homeostasis in hepatic metabolism of glucose, lipids, bile acid, and xenobiotics.…”

Bile Acids Regulate Nuclear Receptor (Nur77) Expression and Intracellular Location to Control Proliferation and Apoptosis

“…(B) Viral infections: BAs promoted HCV replication and HBV gene expression during viral hepatitis pathogenesis (4–6). (C) Chemical carcinogenesis: Ethanol increases the synthesis of toxic BAs while aflatoxin B1 induces cholestasis when excreted into bile (7, 8).…”