乙型肝炎病毒 PreS 变异体的隐匿性感染通过产生异常神经酰

StephenW

乙型肝炎病毒 PreS 变异体的隐匿性感染通过产生异常神经酰胺协同促进高脂饮食环境下肝细胞癌的发展

    刘畅、陈坤、赵飞、宣玲玲、王玉婷、徐春桂、吴志远、王冬梅和曲春风

BMC Medicine 第 20 卷，文章编号：279 (2022) 引用本文

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抽象的
背景

一些隐匿性乙型肝炎病毒 (HBV) 感染是由减少包膜蛋白 (HBsAg) 分泌的 PreS 突变引起的。我们研究了从 HBsAg 血清阴性肝细胞癌 (HCC) 患者中分离的 PreS 变异体感染的肝细胞中神经酰胺的数量和种类，以及神经酰胺对小鼠模型中本土 HCC 发展的影响。
方法

对来自 35 名 HBsAg 血清阴性 HCC 患者的 HBV PreS/S 区域进行了测序。用两种 PreS 变体代表转染肝细胞系和雄性 C57BL/6J 小鼠肝脏。定量具有不同长度的脂肪酰基链的神经酰胺。在喂食不同饮食类型的HBV转染小鼠中检查肿瘤发展。
结果

在 HBsAg 血清阴性 HCC 患者中，非肿瘤性肝组织含有 HBsAg 和具有复制能力的 HBV。与来自一名 HBsAg 血清阴性 HCC 患者的分离株相比，最常检测到的 PreS/S 变体携带 HBsAg 中氨基酸特性改变的突变。 PreS 变体的肝细胞感染导致内质网内的 HBsAg 滞留并产生更多量的神经酰胺，其中 C16:0 神经酰胺升高最高。饱和脂肪酸加重受 PreS 变异体感染的肝细胞产生异常数量和种类的神经酰胺，这些神经酰胺与 HBV 蛋白协同激活肝脏炎性巨噬细胞中的 NLRP3 炎性体。仅在喂食高脂肪饮食的 HBV 转染小鼠中检测到肝肿瘤，转染 PreS 变体的肿瘤负荷较高，与神经酰胺生成异常有关。
结论

改变包膜蛋白氨基酸特性的 HBV PreS 突变抑制了 HBsAg 的分泌。 PreS 变异体感染肝细胞会产生异常的神经酰胺，这些神经酰胺与 HBV 蛋白共同激活肝巨噬细胞中的 NLRP3 炎性体，从而促进原发性 HCC 的发展。

StephenW

Occult infection with hepatitis B virus PreS variants synergistically promotes hepatocellular carcinoma development in a high-fat diet context by generating abnormal ceramides

    Chang Liu, Kun Chen, Fei Zhao, Lingling Xuan, Yuting Wang, Chungui Xu, Zhiyuan Wu, Dongmei Wang & Chunfeng Qu

BMC Medicine volume 20, Article number: 279 (2022) Cite this article

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Abstract
Background

Some occult hepatitis B virus (HBV) infections are resulted from PreS mutations that reduce secretion of envelope protein (HBsAg). We investigated the ceramide amounts and species in hepatocytes infected with PreS variants that were isolated from HBsAg-seronegative patients with hepatocellular carcinoma (HCC) and the ceramide effects on autochthonous HCC development in murine models.
Methods

HBV PreS/S regions from 35 HBsAg-seronegative HCC patients were sequenced. Hepatocyte cell lines and male C57BL/6J mouse livers were transfected with two PreS variant representatives. The ceramides with variated lengths of fatty acyl chains were quantified. Tumour development was examined in the HBV-transfected mice fed different diet types.
Results

In HBsAg-seronegative HCC patients, nonneoplastic liver tissues harboured HBsAg and replication-competent HBV. The most frequently detected PreS/S variants carried mutations of altered amino acid properties in HBsAg compared with an isolate from one HBsAg-seronegative HCC patient. Hepatocyte infection with PreS variants caused HBsAg retention within the endoplasmic reticulum and generated more amounts of ceramides with C16:0 ceramide elevated the highest. Saturated fatty acids aggravated the PreS variant-infected hepatocytes to generate abnormal amounts and species of ceramides, which with HBV proteins synergistically activated NLRP3 inflammasome in liver inflammatory macrophages. Liver tumours were only detected in HBV-transfected mice fed high-fat diet, with higher tumour loads in the PreS variant-transfected, associated with abnormal ceramide generation.
Conclusions

HBV PreS mutations which altered amino acid properties of envelope proteins inhibited HBsAg secretion. Hepatocyte infection with PreS variants generated abnormal ceramides which with HBV proteins coactivated NLRP3 inflammasome in liver macrophages to promote autochthonous HCC development.

StephenW

https://bmcmedicine.biomedcentra ... /s12916-022-02481-3