Z Gastroenterol 2014; 52 - P_5_46
DOI: 10.1055/s-0033-1361055

The expression profile of bile acid and cholesterol synthesis genes are affected by the binding of Hepatitis B Virus to its cellular receptor

N Oehler 1, T Volz 1, J Kah 1, K Giersch 1, L Allweiss 1, J Petersen 2, AW Lohse 1, M Lütgehetmann 4, J Heeren 5, M Dandri 1
  • 1Universitätsklinikum Hamburg-Eppendorf, I. Medizinische Klinik, Zentrum Innere Medizin, Hamburg, Germany
  • 2Asklepios Clinic St. Georg, Hamburg, IFI Institute for Interdisciplinary Medicine, Hamburg, Germany
  • 3Deutsche Zentrum für Infektionsforschung, Standort Hamburg-Lübeck-Borstel, Hamburg-Lübeck-Borstel, Germany
  • 4Universitätsklinikum Hamburg-Eppendorf, Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Hamburg, Germany
  • 5Universitätsklinikum Hamburg-Eppendorf, Institut für Biochenie und Molekulare Zellbiologie, Hamburg, Germany

Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism, suggesting that HBV may affect the expression of metabolism-related genes. Moreover, the sodium-taurocholate cotransporting polypeptide (NTCP), responsible for bile acid uptake into hepatocytes, was identified as the functional cellular receptor mediating HBV entry. Aim of the study was to determine whether HBV alters the liver metabolic profile by employing HBV-infected and uninfected human-liver chimeric mice. Methods: humanized uPA/SCID mice were used to establish chronic HBV infection. Gene expression profiles were determined by RT-PCR using primers specifically recognizing transcripts of either human or murine origin. Liver biopsy samples obtained from HBV-chronic individuals were used to validate changes determined in mice. Results: HBV-infected mice displayed modest changes in lipid metabolism. In contrast, significant upregulation of genes involved in transcriptional regulation, biosynthesis and uptake of cholesterol (SREBP2, p = 0.0001; HMG-CoA reductase, p = 0.0009; LDL receptor, p = 0.001) was determined in HBV-infected mice compared to uninfected controls. The most remarkable change was the enhancement of cholesterol 7α-Hydroxylase (CYP7A1; median 12-fold induction; p < 0.0001), the rate-limiting enzyme promoting cholesterol conversion to bile acids in hepatocytes. Significant CYP7A1 induction (p = 0.002) was confirmed in liver biopsies from HBV-infected patients. Notably, we found that administration of a lipopeptide derived from the preS1-domain of HBV envelope provoked a comparable CYP7A1 induction in uninfected mice, thus designating the preS1-domain as the viral component triggering compensatory cholesterol and bile acid synthesis. Conclusion: Binding of HBV to its cellular receptor NTCP appears to limit the hepatocellular uptake of bile acids. As a means of compensation, bile acid synthesis and consequently provision of cholesterol are induced.