Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism
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Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. / Oehler, Nicola; Volz, Tassilo; Bhadra, Oliver D; Kah, Janine; Allweiss, Lena; Giersch, Katja; Bierwolf, Jeanette; Riecken, Kristoffer; Pollok, Jörg M; Lohse, Ansgar W; Fehse, Boris; Petersen, Joerg; Urban, Stephan; Lütgehetmann, Marc; Heeren, Joerg; Dandri, Maura.
In: HEPATOLOGY, 08.04.2014.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism
AU - Oehler, Nicola
AU - Volz, Tassilo
AU - Bhadra, Oliver D
AU - Kah, Janine
AU - Allweiss, Lena
AU - Giersch, Katja
AU - Bierwolf, Jeanette
AU - Riecken, Kristoffer
AU - Pollok, Jörg M
AU - Lohse, Ansgar W
AU - Fehse, Boris
AU - Petersen, Joerg
AU - Urban, Stephan
AU - Lütgehetmann, Marc
AU - Heeren, Joerg
AU - Dandri, Maura
N1 - © 2014 by the American Association for the Study of Liver Diseases.
PY - 2014/4/8
Y1 - 2014/4/8
N2 - Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na(+) -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 HBV-chronic 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 7α-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-methylglutaryl-coenzyme 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 viral-drug interactions. (Hepatology 2014).
AB - Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na(+) -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 HBV-chronic 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 7α-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-methylglutaryl-coenzyme 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 viral-drug interactions. (Hepatology 2014).
U2 - 10.1002/hep.27159
DO - 10.1002/hep.27159
M3 - SCORING: Journal article
C2 - 24711282
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
ER -