Bile acids promote the expression of hepatitis C virus in replicon-harboring cells.
Hepatitis C virus (HCV) is a cause of chronic liver disease, with more than 170 million persistently infected individuals worldwide. Although the combination therapy of alpha interferon (IFN-alpha) and ribavirin is effective for chronic HCV infection, around half of all patients infected with HCV genotype 1 fail to show sustained virologic responses and remain chronically infected. Previously, we demonstrated that bile acids were essential for growth of porcine enteric calicivirus in cell culture in association with down-regulation of IFN responses. Because hepatocytes are exposed to high concentrations of bile acids in the liver, we hypothesized that bile acids have similar effects on HCV replication. We incubated HCV replicon-harboring cells (genotype 1b, Con1) in the presence of various bile acids and monitored the expression of HCV RNA and protein (NS5B). The addition of an individual bile acid (deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or glycochenodeoxycholic acid) in the medium increased the levels of HCV RNA and proteins up to fivefold at 48 h of incubation. An antagonist of bile acid receptor farnesoid X receptor (FXR), Z-guggulsterone, reduced the bile acid-mediated increase of HCV RNA. When IFN (alpha or gamma) and each bile acid were incubated together, we observed that bile acid significantly reduced the anti-HCV effect of IFN. These results indicated that bile acids are factors in the failure of IFN treatment for certain patients infected with HCV genotype 1. Our finding may also contribute to the establishment of better regimens for treatment of chronic HCV infections by including agents altering the bile acid-mediated FXR pathway.
Chang
Kyeong-Ok
KO
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS 66506, USA. kchang@vet.ksu.edu
George
David W
DW
D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000494:pharmacology; D011282:Pregnenediones / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D012093:Replicon / Q000502:physiology; D012254:Ribavirin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014720:Vesicular Exanthema of Swine / Q000378:metabolism; D017928:Vesicular exanthema of swine virus / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
D000998:Antiviral Agents; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007371:Interferon-gamma; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D012254:Ribavirin; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione