Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism

Abstract

Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na 1 -taurocholate cotransporting polypeptide (NTCP), responsible for bile acid (BA) uptake into hepatocytes, was identified as the functional cellular receptor mediating HBV entry. The aim of the study was to determine whether HBV alters the liver metabolic profile by employing HBV-infected and uninfected human liver chimeric mice. Humanized urokinase plasminogen activator/severe combined immunodeficiency mice were used to establish chronic HBV infection. Gene expression profiles were determined by real-time polymerase chain reaction using primers specifically recognizing transcripts of either human or murine origin. Liver biopsy samples obtained from HBVchronic individuals were used to validate changes determined in mice. Besides modest changes in lipid metabolism, HBV-infected mice displayed a significant enhancement of human cholesterol 7a-hydroxylase (human [h]CYP7A1; median 12-fold induction; P < 0.0001), the rate-limiting enzyme promoting the conversion of cholesterol to BAs, and of genes involved in transcriptional regulation, biosynthesis, and uptake of cholesterol (human sterol-regulatory element-binding protein 2, human 3-hydroxy-3-methylglutarylcoenzyme A reductase, and human low-density lipoprotein receptor), compared to uninfected controls. Significant hCYP7A1 induction and reduction of human small heterodimer partner, the corepressor of hCYP7A1 transcription, was also confirmed in liver biopsies from HBV-infected patients. Notably, administration of Myrcludex-B, an entry inhibitor derived from the pre-S1 domain of the HBV envelope, provoked a comparable murine CYP7A1 induction in uninfected mice, thus designating the pre-S1 domain as the viral component triggering such metabolic alterations. Conclusion: Binding of HBV to NTCP limits its function, thus promoting compensatory BA synthesis and cholesterol provision. The intimate link determined between HBV and liver metabolism underlines the importance to exploit further metabolic pathways, as well as possible NTCP-related viraldrug interactions.

Mechanism of Hepatitis B Virus Persistence in Hepatocytes and Its Carcinogenic Potential

“…On the other hand, interactions between viral components and cellular factors may also impact the liver metabolism. Recent studies showed that binding of the preS1 domain of the large envelope protein of HBV limits the hepatocellular uptake of bile salts [79,80] and the expression profile of key genes involved in bile acid metabolism [81]. These findings suggest that in the setting of chronic HBV infection, alterations of the hepatocellular uptake of bile acids may lead to different levels of compensatory metabolic alterations and also promote disease progression.…”

Lentiviral hepatitis B pseudotype entry requires sodium taurocholate co-transporting polypeptide and additional hepatocyte-specific factors

“…1e). HBV Pre-S1 engagement of NTCP has been reported to alter the expression of genes involved in bile acid metabolism (Oehler et al, 2014), and these pathways may play a role in promoting the assembly and/or secretion of pseudoparticles.…”

Bile Acid Uptake Transporters as Targets for Therapy

“…The (metabolic) consequences of this action are currently not clear, although some first insights were obtained using a mouse model, where human hepatocytes repopulated the liver of urokinase plasminogen activator/severe combined immunodeficiency mice. NTCP inhibition using myrcludex B resulted in increased CYP7A1 expression, suggesting reduced FXR activity [82]. Chronic HBV infection in these humanized mice had a similar effect.…”