HBV引起的细胞内胆固醇积累诱导atf6介导的内质网应激触发内质网吞噬。

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-09-09 DOI:10.1016/j.tice.2025.103134

Yongxu Lin , Pingying Jiang , Weiqi Cai , Yongzhu Huang , Qiuyan Lin , Mingrong Wang , Fenglin Chen , Yuanlin Qi , Dan Li

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引用次数: 0

摘要

背景：乙型肝炎病毒（HBV）感染可引起胆固醇积累，诱导内质网应激（ERS），增强肝细胞自噬。然而，这些相互作用的机制尚不清楚，以及慢性乙型肝炎（CHB）患者降胆固醇治疗的潜在益处。因此，本研究探讨HBV引起的胆固醇积累对ERS和自噬的影响，旨在确定介导ERS与内质网吞噬（endoplasmic reticulophagy, ER-phagy）之间串扰的关键分子。方法：采用生物信息学、免疫组化（IHC）、蛋白质组学、western blot、透射电镜（TEM）等方法对临床标本、HBV转基因动物和细胞模型进行分析。结果：GEO数据库分析显示，CHB组织中LDLR、SREBF2/SREBP2、ATF6、MAP1LC3B/LC3B和SQSTM1/P62的转录水平高于正常肝组织。免疫组化结果显示，CHB组织中LDLR、SREBP2、GRP78、ATF6、LC3B、P62和FAM134B的表达高于正常肝组织。HBV转基因小鼠和HepG2.2.15细胞肝脏游离胆固醇含量、GRP78、ATF6、LC3B II、P62和FAM134B的表达均高于对照组。透射电镜显示，在HBV转基因小鼠和HepG2.2.15细胞的肝脏中，内质网（ER）扩张、脱颗粒，以及ER吞噬。此外，在HBV转基因小鼠和HepG2.2.15细胞中，褪黑素（ATF6抑制剂）可减轻肝脏炎症，减轻ERS，下调ATF6表达，抑制er吞噬。在HBV转基因小鼠和HepG2.2.15细胞中，给予胆固醇合成抑制剂Fatostatin可减轻肝脏炎症，降低游离胆固醇含量，减轻ERS，下调GRP78和ATF6表达，抑制er吞噬。结论：HBV感染可导致肝细胞内胆固醇积累，促进ATF6介导的ERS和fam134b介导的er吞噬。减少细胞内胆固醇积累可减轻atf6介导的ERS，抑制fam134b介导的er吞噬，减轻肝脏炎症。ATF6可能是CHB辅助治疗的一个有希望的治疗靶点。我们的研究为他汀类药物作为慢性乙型肝炎的辅助治疗提供了实验证据。

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Intracellullar cholesterol accumulation caused by HBV induces ATF6-mediated endoplasmic reticulum stress to trigger endoplasmic reticulophagy

Backgroud

Hepatitis B virus (HBV) infection can cause cholesterol accumulation, induce endoplasmic reticulum stress (ERS) and enhance autophagy in hepatocytes. However, the mechanisms underlying these interactions remain unclear, as well as the potential benefit of cholesterol-lowering treatment in patients with chronic hepatitis B (CHB). Therefore, the effects of of cholesterol accumulation caused by HBV on ERS and autophagy were explored in this study, aiming to identify the key molecules mediating the crosstalk between ERS and endoplasmic reticulophagy (ER-phagy).

Methods

Bioinformatics, immunohistochemistry (IHC), proteomics, western blot, and transmission electron microscopy (TEM) were used to analyse clinical specimens, HBV transgenic animal and cell models.

Results

Analysis of Gene Expression Omnibus (GEO) database demonstrated that the transcription levels of LDLR, SREBF2/SREBP2, ATF6, MAP1LC3B/LC3B and SQSTM1/P62 in CHB tissues were higher than those in normal liver tissues. The IHC results showed that the expressions of LDLR, SREBP2, GRP78, ATF6, LC3B, P62 and FAM134B in CHB tissues were higher than those in normal liver tissues. The free cholesterol content, the expression of GRP78, ATF6, LC3B II, P62 and FAM134B were higher in the livers of HBV transgenic mice and HepG2.2.15 cells compared with their control groups. TEM showed endoplasmic reticulum (ER) expansion and degranulation, as well as ER-phagy, in the livers of HBV transgenic mice and HepG2.2.15 cells. Furthermore, melatonin administration, an ATF6 inhibitor, attenuated hepatic inflammation, alleviated ERS, downregulated ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells. Fatostatin administration, a cholesterol synthesis inhibitor, attenuated hepatic inflammation, decreased the free cholesterol content, alleviated ERS, downregulated GRP78 and ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells

Conclusion

HBV infection leads to cholesterol accumulation in hepatocytes, which promotes ATF6-mediated ERS and FAM134B-mediated ER-phagy. Reducing intracellular cholesterol accumulation alleviates ATF6-mediated ERS, inhibits FAM134B-mediated ER-phagy, and attenuates hepatic inflammation. ATF6 may represent a promising therapeutic target for an adjuvant treatment of CHB. Our study provides experimental evidence for the use of statin as an adjuvant treatment of CHB.

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.