Limited Effects of Bile Acids and Small Heterodimer Partner on Hepatitis B Virus Biosynthesis In Vivo

Abstract

Multiple nuclear receptors, including hepatocyte nuclear factor 4␣ (HNF4␣), retinoid X receptor ␣ (RXR␣) plus peroxisome proliferator-activated receptor ␣ (PPAR␣), RXR␣ plus farnesoid X receptor ␣ (FXR␣), liver receptor homolog 1 (LRH1), and estrogen-related receptors (ERRs), have been shown to support efficient viral biosynthesis in nonhepatoma cells in the absence of additional liver-enriched transcription factors. Although HNF4␣ has been shown to be critical for the developmental expression of hepatitis B virus (HBV) biosynthesis in the liver, the relative importance of the various nuclear receptors capable of supporting viral transcription and replication in the adult in vivo has not been clearly established. To investigate the role of the nuclear receptor FXR and the corepressor small heterodimer partner (SHP) in viral biosynthesis in vivo, SHP-expressing and SHP-null HBV transgenic mice were fed a bile acid-supplemented diet. The increased FXR activity and SHP expression levels resulting from bile acid treatment did not greatly modulate HBV RNA and DNA synthesis. Therefore, FXR and SHP appear to play a limited role in modulating HBV biosynthesis, suggesting that alternative nuclear receptors are more critical determinants of viral transcription in the HBV transgenic mouse model of chronic viral infection. These observations suggest that hepatic bile acid levels or therapeutic agents targeting FXR may not greatly modulate viremia during natural infection. H epatitis B virus (HBV) biosynthesis is restricted primarily to the liver (15). This tropism presumably reflects the limited tissue distribution of the viral receptor, although the entry mechanism and proteins involved have not been defined (12). However, the tissue tropism of HBV is also restricted at the level of transcription (15). Liver-enriched transcription factors, and nuclear receptors in particular, have been shown to be essential for viral RNA synthesis (19,44,47,52,53,61). As HBV replicates by the reverse transcription (RT) of the pregenomic 3.5-kb RNA synthesized from the nucleocapsid or core promoter (58), it is apparent that transcription is a major regulatory step governing viral biosynthesis (53). In the context of viral replication, the nuclear receptors hepatocyte nuclear factor 4␣ (HNF4␣), retinoid X receptor ␣ (RXR␣) plus peroxisome proliferator-activated receptor ␣ (PPAR␣), RXR␣ plus farnesoid X receptor ␣ (FXR␣), liver receptor homolog 1 (LRH1), and estrogen-related receptor (ERR) have been shown to be the only transcription factors capable of supporting pregenomic RNA synthesis and viral replication in nonhepatoma cells in the absence of any additional complementing transcriptional regulatory machinery (44, 53). These observations suggest that nuclear receptors have a unique capacity to support HBV transcription and replication. However, the relative importance of the various nuclear receptors in governing HBV biosynthesis in vivo has not been extensively investigated (14,24). Additionally the coactivator peroxisome proliferator-act...

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

“…Similarly, bile acids can activate HBV biosynthesis to a limited extent in vivo under certain circumstances (11). Together these findings suggest that ligand-activated nuclear receptor-mediated HBV biosynthesis may represent a proportion of the virus production occurring during natural infection, whereas the remainder of the HBV RNA and DNA synthesis is probably mediated by orphan nuclear receptors (11) plus additional classes of liver-enriched and ubiquitous transcription factors (3).…”

“…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).…”

The Hepatitis B Virus Receptor

“…FXR may bind to two response elements in the HBV core promoter region, and its activation by ligands regulates promoter activity of the HBV core (Kim et al 2010, Ramiere et al 2008. 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).…”

Bile acid-induced modulation of virus replication

“…Hepatitis B virus (HBV) only replicates in the liver, probably due to the fact that NTCP is the entry receptor for HBV and replication is dependent on liver enriched transcription factors as hepatocyte nuclear factor 4α, liver receptor homolog 1, estrogen-related receptor or heterodimers of retinoid X receptor (RXRα) with FXRα or peroxisome proliferator- activated receptor [6]. Two binding sites of FXR and RXRα heterodimers are localized in the HBV enhancer 2 and core promoter region.…”