脂质储存和干扰素反应决定了小鼠和人类中毛玻璃肝细胞的

StephenW

Lipid storage and interferon response determine the phenotype of ground glass hepatocytes in mice and humans
Yuri Churin  1 , Karuna Irungbam  2 , Christoph S Imiela  2 , David Schwarz  2 , Hans-Joachim Mollenkopf  3 , Uta Drebber  4 , Margarete Odenthal  4 , Oleg Pak  5 , Magdalena Huber  6 , Dieter Glebe  7 , Martin Roderfeld  2 , Elke Roeb  8
Affiliations
Affiliations

    1
    Department of Gastroenterology, Justus Liebig University, Giessen, Germany; Current address: Institute for Veterinary Food Science, Faculty of Veterinary Medicine, Justus Liebig University, Giessen, Germany.
    2
    Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
    3
    Core Facility Microarray, Max Planck Institute for Infection Biology, Berlin, Germany.
    4
    Institute for Pathology, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
    5
    Excellence Cluster Cardiopulmonary System, University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University, Giessen, Germany.
    6
    Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany.
    7
    Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University Giessen, Giessen, Germany.
    8
    Department of Gastroenterology, Justus Liebig University, Giessen, Germany. Electronic address: [email protected].

    PMID: 33766783 DOI: 10.1016/j.jcmgh.2021.03.009

Abstract

Background and aims: A histopathological hallmark of chronic hepatitis B virus (HBV) infection is the presence of ground glass hepatocytes (GGHs). GGHs are liver cells that exhibit eosinophilic, granular, glassy cytoplasm in light microscopy and are characterized by accumulation of HBV surface (HBs) proteins in the endoplasmic reticulum (ER). More important, GGHs have been accepted as a precursor of HCC and may represent preneoplastic lesions of the liver.

Methods: Here we show that the reason for ground glass phenotype of hepatocytes in patients with chronic hepatitis B (CHB) and in HBs transgenic mice is a complex formation between HBs proteins and lipid droplets (LDs) within the ER.

Results: As fat is a main component of LDs their presence reduces the protein density of HBs aggregates. Therefore, they adsorb less amount of eosin during hematoxylin-eosin staining and appear dull in light microscopy. However, after induction of interferon response in the liver LDs were not only co-localized with HBs but also distributed throughout the cytoplasm of hepatocytes. The uniform distribution of LDs weakens the contrast between HBs aggregates and the rest of the cytoplasm and complicates the identification of GGHs. Suppression of interferon response restored the ground glass phenotype of hepatocytes.

Conclusion: Complex formation between HBs and LDs represents a very important feature of CHB that could affect LDs functions in hepatocytes. The strain specific activation of the interferon response in the liver of HBs/c mice prevented the development of GGHs. Thus, manipulation of LDs could provide a new treatment strategy in the prevention of liver cancer.

Keywords: GGH; Heptitis B; intracellular aggregates; surface proteins.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

StephenW

脂质储存和干扰素反应决定了小鼠和人类中毛玻璃肝细胞的表型
Yuri Churin 1，Karuna Irungbam 2，Christoph S Imiela 2，David Schwarz 2，Hans-Joachim Mollenkopf 3，Uta Drebber 4，Margarete Odenthal 4，Oleg Pak 5，Magdalena Huber 6，Dieter Glebe 7，Martin Roderfeld 2，Elke Roeb 8
隶属关系
隶属关系

    1个
    德国吉森贾斯图斯·利比格大学胃肠病学系；当前地址：德国吉森贾斯图斯·利比格大学兽医学院兽医食品科学研究所。
    2个
    德国吉森Justus Liebig大学胃肠病学系。
    3
    核心设施微阵列，马克斯·普朗克感染生物学研究所，德国柏林。
    4
    德国科隆大学医院病理学研究所；德国科隆大学分子医学中心。
    5
    吉森大学的卓越集群心肺系统和德国吉森的Justus Liebig大学的马尔堡肺中心（UGMLC）。
    6
    德国马尔堡马尔堡大学医学微生物学和医院卫生学研究所。
    7
    吉斯贾斯图斯·利比格大学，德国吉森，医学病毒学研究所，国家乙型和丁型肝炎病毒参考中心。
    8
    德国吉森Justus Liebig大学胃肠病学系。电子地址：[email protected]。

    PMID：33766783 DOI：10.1016 / j.jcmgh.2021.03.009

抽象的

背景与目的：慢性乙型肝炎病毒（HBV）感染的组织病理学特征是存在毛玻璃肝细胞（GGH）。 GGH是在光学显微镜下表现出嗜酸性粒状玻璃状细胞质的肝细胞，其特征在于内质网（ER）中HBV表面（HBs）蛋白的积累。更重要的是，GGH已被接受为HCC的前体，可能代表肝脏的肿瘤前病变。

方法：在这里，我们表明，慢性乙型肝炎（CHB）和HBs转基因小鼠肝细胞玻璃样表型的原因是ER内HBs蛋白和脂质滴（LDs）之间形成复杂的形成。

结果：由于脂肪是LD的主要成分，因此脂肪的存在会降低HBs聚集体的蛋白质密度。因此，它们在苏木精-曙红染色过程中吸附的曙红数量较少，并且在光学显微镜下显得暗淡无光。然而，在肝脏中干扰素诱导后，LDs不仅与HBs共定位，而且分布在肝细胞的整个细胞质中。 LDs的均匀分布会削弱HBs聚集体与其余细胞质之间的对比度，并使GGH的鉴定复杂化。干扰素反应的抑制恢复了肝细胞的毛玻璃表型。

结论：HBs和LDs之间的复合物形成是CHB的一个非常重要的特征，它可能影响LDs在肝细胞中的功能。 HBs / c小鼠肝脏中干扰素应答的菌株特异性激活阻止了GGH的发展。因此，LDs的操作可以为预防肝癌提供新的治疗策略。

关键字：GGH;乙型肝炎；细胞内聚集体；表面蛋白。

版权所有©2021作者。由Elsevier Inc.出版。保留所有权利。

StephenW

https://www.cmghjournal.org/article/S2352-345X(21)00061-8/pdf