脂肪酶抑制剂奥利司他通过靶向病毒生命周期中的早期步骤

StephenW

Antiviral Res. 2018 Jan 5. pii: S0166-3542(17)30602-2. doi: 10.1016/j.antiviral.2018.01.001. [Epub ahead of print]
Lipase inhibitor orlistat prevents hepatitis B virus infection by targeting an early step in the virus life cycle.
Esser K1, Lucifora J2, Wettengel J1, Singethan K1, Glinzer A3, Zernecke A4, Protzer U5.
1
    Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Munich, Germany.
2
    Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich site, Germany.
3
    Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universität München, Germany.
4
    Institute of Experimental Biomedicine, University Hospital Würzburg, Josef-Schneider-Str. 2, Würzburg, 97080, Germany.
5
    Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich site, Germany. Electronic address: [email protected]
Abstract

Hepatitis B Virus (HBV) is a strictly hepatotropic pathogen which is very efficiently targeted to the liver and into its host cell, the hepatocyte. The sodium taurocholate co-transporting polypeptide (NTCP) has been identified as a key virus entry receptor, but the early steps in the virus life cycle are still only barely understood. Here, we investigated the effect of lipase inhibition and lipoprotein uptake on HBV infection using differentiated HepaRG cells and primary human hepatocytes. We found that an excess of triglyceride rich lipoprotein particles in vitro diminished HBV infection and a reduced hepatic virus uptake in vivo if apolipoprotein E is lacking indicating virus transport along with lipoproteins to target hepatocytes. Moreover, we showed that HBV infection of hepatocytes was inhibited by the broadly active lipase inhibitor orlistat, approved as a therapeutic agent which blocks neutral lipid hydrolysis activity. Orlistat treatment targets HBV infection at a post-entry step and inhibited HBV infection during virus inoculation strongly in a dose-dependent manner. In contrast, orlistat had no effect on HBV gene expression or replication or when added after HBV infection. Taken together, our data indicate that HBV connects to the hepatotropic lipoprotein metabolism and that inhibition of cellular hepatic lipase(s) may allow to target early steps of HBV infection.

PMID:
    29309795
DOI:
    10.1016/j.antiviral.2018.01.001

StephenW

抗病毒研究2018年1月5日。pii：S0166-3542（17）30602-2。 doi：10.1016 / j.antiviral.2018.01.001。 [电子版提前打印]
脂肪酶抑制剂奥利司他通过靶向病毒生命周期中的早期步骤来预防乙型肝炎病毒感染。
Esser K1，Lucifora J2，Wettengel J1，Singethan K1，Glinzer A3，Zernecke A4，Protzer U5。
    慕尼黑工业大学病毒学研究所/ Helmholtz ZentrumMünchen，Trogerstrasse 30，81675，德国慕尼黑。
2
    慕尼黑工业大学病毒学研究所/ Helmholtz ZentrumMünchen，Trogerstrasse 30，81675，德国慕尼黑;德国慕尼黑现场感染研究中心（DZIF）。
3
    德国慕尼黑工业大学血管和血管内外科，Klinikum rechts der Isar der TechnischenUniversitätMünchen，德国。
4
    维尔茨堡大学附属医院实验生物医学研究所，Josef-Schneider-Str。 2，Würzburg，97080，德国。
五
    慕尼黑工业大学病毒学研究所/ Helmholtz ZentrumMünchen，Trogerstrasse 30，81675，德国慕尼黑;德国慕尼黑现场感染研究中心（DZIF）。电子地址：[email protected]
抽象

乙型肝炎病毒（HBV）是一种严格的肝向性病原体，其非常有效地靶向肝脏和其宿主细胞即肝细胞。牛磺胆酸钠共转运多肽（NTCP）已被确定为关键的病毒进入受体，但病毒生命周期的早期阶段仍然只有勉强的了解。在这里，我们使用分化的HepaRG细胞和原代人肝细胞研究了脂肪酶抑制和脂蛋白摄取对HBV感染的影响。我们发现体外富含甘油三酯的脂蛋白颗粒的过量减少了HBV感染，并且如果载脂蛋白E缺乏表明病毒与脂蛋白一起靶向肝细胞，则体内肝脏病毒摄取减少。此外，我们还发现广泛活性的脂肪酶抑制剂奥利司他抑制了肝细胞的HBV感染，被批准用作阻断中性脂质水解活性的治疗剂。奥利司他治疗以入侵后的HBV感染为目标，在病毒接种期间以剂量依赖的方式强烈抑制HBV感染。相反，奥利司他对HBV基因表达或复制无影响，或在HBV感染后加入。综上所述，我们的数据表明，HBV与肝嗜酸性脂蛋白代谢相关，并且抑制细胞肝脂肪酶可以允许靶向早期的HBV感染步骤。

结论：
    29309795
DOI：
    10.1016 / j.antiviral.2018.01.001