1) BA nuclear receptor FXR binds to two response elements in the

1) BA nuclear receptor FXR binds to two response elements in the HBV core promoter region and its activation by ligands regulates the HBV core promoter AZD9291 research buy activity 2) HBx binds to Sirt-1, a deacetylase that regulates FXR activity and to PRMT1 transmethylase that is recruited by FXR upon its activation 3) the Na1-taurocholate cotransporting polypeptide (NTCP) responsible of BA uptake was identified as

a functional receptor for HBV and 4) reciprocally competition between virus and BA for NTCP induces a compensatory BA synthesis. We aimed at investigating the effect of FXR on HBV replication. First we screen HBV proteins interaction with FXR and found that among the HBV proteins, HBx was co-immunoprecipitated with FXR. Second we tested the effect of FXR modulators on HBV replication. Differentiated HepaRG cells that support a complete

replication cycle were infected with HBV and treated from day 2 to 10 post infection with FXR modulators. Treatment with BA derived 6-ethyl-chenodeoxycholic acid (6-ECDCA) or synthetic non-steroidal agonists, but not with antagonists or ursodeoxycholic acid, strongly inhibited the secretion of HBV DNA, HBsAg, HBeAg and of HBcAg synthesis Y-27632 order in a dose dependent manner (70 to 80 %inhibition at 1 or 10 micro-Mol) as well as the viral pregenomic RNA synthesis, cccDNA copies number and cellular total HBV DNA. Cyclosporine A, an NTCP ligand and HBV entry inhibitor, did not modify the effect of agonists suggesting that the effect did not depend on entry inhibition. Treatment consistently increased FXR activity as indicated by the increase of the small heterodimer partner (SHP) and decrease

of the apolipoprotein-A1 mRNAs expression, two FXR dependent genes, despite medchemexpress reduced FXR mRNA levels. In conclusion, BA-derived or synthetic agonists lead to a sustained repression of HBV replication in the HepaRG cell culture system. This effect is likely mediated by a modulation of FXR activation that could perturb the complex FXR network of transcription factors, which is highly targeted and controlled by HBx rather than by a competition between the virus and FXR agonist for NTCP and inhibition of virus entry. These data stress out the importance to exploit drug regulation of metabolism pathways in controlling HBV replication.

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>