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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-77699
URL: http://ediss.sub.uni-hamburg.de/volltexte/2016/7769/


Das "Metabolovirus" HBV : Auswirkungen einer chronischen Hepatitis B-Infektion auf den hepatozellulären Lipid-, Cholesterin- und Gallensäuremetabolismus

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

Oehler, Nicola

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SWD-Schlagwörter: Hepatitis-B-Virus
Freie Schlagwörter (Deutsch): NTCP , Gallensäuremetabolismus
Basisklassifikation: 44.61
Institut: Medizin
DDC-Sachgruppe: Medizin, Gesundheit
Dokumentart: Dissertation
Hauptberichter: Dandri, Maura (Prof. Dr.)
Sprache: Mehrsprachig
Tag der mündlichen Prüfung: 16.02.2016
Erstellungsjahr: 2015
Publikationsdatum: 02.03.2016
Kurzfassung auf Deutsch: Über die Erforschung der Auswirkungen einer chronischen Hepatitis B-Infektion auf den hepatozellulären Lipid-, Cholesterin- und Gallensäuremetabolismus sowie deren zugrunde liegende molekulare Mechanismen und intrazelluläre Signalwege in humanisierten chimären uPA/SCID/beige Mäusen.
Kurzfassung auf Englisch: Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. 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: Besides modest changes in lipid metabolism, HBV-infected mice displayed a significant enhancement of human cholesterol 7α-Hydroxylase (hCYP7A1; median 12-fold induction; p<0.0001), the rate-limiting enzyme promoting the conversion of cholesterol to bile acids, and of genes involved in transcriptional regulation, biosynthesis and uptake of cholesterol (hSREBP2, hHMG-CoA reductase, hLDL receptor) compared to uninfected controls. Significant hCYP7A1 induction and reduction of hSHP, the co-repressor of hCYP7A1 transcription, was also confirmed in liver biopsies from HBV-infected patients. Notably, administration of Myrcludex-B, an entry inhibitor derived from the preS1-domain of HBV envelope, provoked a comparable mCYP7A1 induction in uninfected mice, thus designating the preS1-domain as the viral component triggering such metabolic alterations. Conclusion: Binding of HBV to NTCP limits its function, thus promoting compensatory bile acid 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.

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