Transactivation of the Hepatitis B Virus Core Promoter by the Nuclear Receptor FXRα

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...

Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 98%

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

Reese

Moore

McLachlan

2012

“…Long-chain fatty acids are ligands for peroxisome proliferator-activated receptor ␣ (PPAR␣), which links HBV biosynthesis to energy homeostasis (9). Bile acids are ligands for farnesoid X receptor ␣ (FXR␣), further linking HBV biosynthesis to lipid metabolism (29,30). Hepatocyte nuclear factor 4␣ (HNF4␣) and estrogen-related receptor (ERR) are orphan nuclear receptors, which like PPAR␣ and FXR␣ can display alteration in transcriptional activities in response to the coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) and the corepressor small heterodimer partner (SHP) (1,23).…”

mentioning

confidence: 99%

“…In addition, transcription of the viral genome limits HBV biosynthesis to cells expressing the nuclear receptors required for viral pregenomic RNA synthesis and replication (13,40). The nuclear receptors present in hepatocytes that regulate HBV transcription include both liganddependent and orphan nuclear receptors which lack known ligands (16,22,30,40). Long-chain fatty acids are ligands for peroxisome proliferator-activated receptor ␣ (PPAR␣), which links HBV biosynthesis to energy homeostasis (9).…”

mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α and Small Heterodimer Partner Differentially Regulate Nuclear Receptor-Dependent Hepatitis B Virus Biosynthesis

Ondracek

Rushing

Reese

et al. 2009

In natural infection, hepatitis B virus (HBV) transcription and replication is essentially restricted to the hepatocytes in the livers of humans and a limited number of primates (15,19,33,36,41). HBV tropism is probably restricted at the level of entry by the viral receptor, which likely has a limited tissue distribution (10, 33). In addition, transcription of the viral genome limits HBV biosynthesis to cells expressing the nuclear receptors required for viral pregenomic RNA synthesis and replication (13,40). The nuclear receptors present in hepatocytes that regulate HBV transcription include both liganddependent and orphan nuclear receptors which lack known ligands (16,22,30,40). Long-chain fatty acids are ligands for peroxisome proliferator-activated receptor ␣ (PPAR␣), which links HBV biosynthesis to energy homeostasis (9). Bile acids are ligands for farnesoid X receptor ␣ (FXR␣), further linking HBV biosynthesis to lipid metabolism (29, 30). Hepatocyte nuclear factor 4␣ (HNF4␣) and estrogen-related receptor (ERR) are orphan nuclear receptors, which like PPAR␣ and FXR␣ can display alteration in transcriptional activities in response to the coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) and the corepressor small heterodimer partner (SHP) (1, 23). PGC1␣ is critical for the activation of liver gluconeogenesis and therefore couples HBV transcription and replication to liver carbohydrate metabolism and whole-body energy homeostasis (43). SHP expression is activated by bile acids via FXR␣ and tumor necrosis factor ␣ through AP1, leading to the inhibition of the activities of multiple nuclear receptors (6,11,14,24). Therefore, SHP may regulate HBV biosynthesis in response to changing lipid metabolism or inflammatory signals within the liver (28).Several nuclear receptors expressed in the liver have been shown to support HBV biosynthesis in nonhepatoma cell lines (see Fig. 1 to 6) (27a, 40). However, it is unclear which of these nuclear receptors are critical to supporting viral transcription and replication in hepatocytes in vivo. Conditional deletion of HNF4␣ in the liver of neonatal HBV transgenic mice demonstrated that this nuclear receptor was essential for viral biosynthesis (21). However, the early developmental loss of HNF4␣ is associated with decreased expression of a variety of additional nuclear receptors capable of supporting viral biosynthesis. Therefore, it is unclear if the loss in HBV transcription and replication observed in the liver-specific HNF4␣-null HBV transgenic mouse is due directly to the loss of HNF4␣ or to the indirect effects on other nuclear receptors (18). Similarly, it is apparent that hepatoma cells can support HBV biosynthesis, but it has not been established which transcription factors present in these cells, but not in nonhepatoma cells, are responsible for supporting viral pregenomic RNA synthesis (4,39,40).Given the importance of nuclear receptors and their associated coactivators and corepressors to liver energy homeostasis,

“…Hepatitis C virus (HCV) and hepatitis B virus (HBV) benefit from bile acid-dependent FXR activation (32,33), while for rotaviruses a significantly reduced fecal shedding was shown at 1 and 3 days postinfection in chenodeoxycholic acid-fed mice (34).…”

mentioning

confidence: 99%

Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

Schupp

Trilling

Rattay

et al. 2016

The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-␣) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-␥. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells. IMPORTANCECytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds. C ytomegaloviruses (CMV) are members of the Betaherpesvirinae subfamily and persist for life in infected individuals during alternating phases of latency and productive reactivation. Seroprevalence studies indicate that the large majority of the global human population is currently infected with human cytomegalovirus (HCMV) (human herpesvirus 5 [HHV-5]; taxonomy ID 10359). Although HCMV-related fatalities in apparently healthy individuals sporadically occur (1, 2), HCMV replication usually remains subclinical. This drastically changes under immunocompromising conditions, where untreated CMV infections often cause overt disease, including hepatitis (3) and dysfunction, bleeding, ulceration, and perforation of organs of the upper as well as lower gastrointestinal tract (4). HCMV hepatitis is particularly common in liver transplant recipients and is associated with organ dysfunction and graft failure (5-9).The species specificity of CMV precludes meaningful in vivo experimentation with HCMV in small animal models. Therefore, the homologous mouse CMV (MCMV) (Murid herpesvirus 1, taxonomy ID 10366), which infects Mus musculus (taxonomy ID 10090) as its natural host, has been estab...