小异二聚体伴侣
胆固醇7α羟化酶
生物
乙型肝炎病毒
还原酶
低密度脂蛋白受体
胆汁酸
分子生物学
胆固醇
核受体
病毒学
内分泌学
病毒
脂蛋白
基因
酶
转录因子
生物化学
作者
Nicola Oehler,Tassilo Volz,Oliver D. Bhadra,Janine Kah,Lena Allweiss,Katja Giersch,Jeanette Bierwolf,Kristoffer Riecken,J. Pollok,Ansgar W. Lohse,Boris Fehse,J. Petersen,Stephan Urban,Marc Lütgehetmann,Joerg Heeren,Maura Dandri
出处
期刊:Hepatology
[Wiley]
日期:2014-05-19
卷期号:60 (5): 1483-1493
被引量:116
摘要
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;60:1483–1493)
科研通智能强力驱动
Strongly Powered by AbleSci AI