Multiple nuclear receptors including hepatocyte nuclear factor 4α (HNF4α), retinoid X receptor α (RXRα) plus peroxisome proliferator-activated receptor α (PPARα), RXRα plus farnesoid X receptor α (FXRα), liver receptor homolog 1 (LRH1) and estrogen related receptors (ERR) have been shown to support efficient viral biosynthesis in nonhepatoma cells in the absence of additional liver-enriched transcription factors. Although HNF4α has been shown to be critical for the developmental expression of 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 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 alternative nuclear receptors are more critical determinants of viral transcription in the HBV transgenic mouse model of chronic viral infection. These observations suggest hepatic bile acid levels or therapeutic agents targeting FXR may not greatly modulate viremia during natural infection. ; The original version is available through American Society for Microbiology at doi: 10.1128/JVI.06742-11 ; This work was supported by Public Health Service grant AI30070 from the National Institutes of Health.