Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes
Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes
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DOI：
10.1007/s00795-009-0476-5
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发表时间：
2010-03-01
影响因子：
1.8
通讯作者：
Harada, Masaru
中科院分区：
文献类型：
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作者：
Harada, Masaru
一些人类肝病与肝细胞Mallory-Denk小体(MDB)的形成有关，MDB由角蛋白和泛素组成。在其他各种疾病、神经退行性疾病和肌肉疾病中也发现了类似的包涵体。然而，MDB的形成机制尚不清楚。自噬是细胞内蛋白质和细胞器的降解过程。在本研究中，我们研究了自噬与MDB形成的关系。我们给野生型和角蛋白8转基因小鼠喂以含3，5-二乙氧基甲酰-1，4-二氢氯仿(DDC)的饲料9天。用免疫组织化学、常规和免疫电子显微镜对肝脏进行分析。短期DDC喂养诱导了角蛋白8转基因小鼠肝脏中的MDB，但不能诱导非转基因小鼠肝脏中的MDB。电子显微镜下可见肝细胞胞浆内由电子致密物质和细丝组成的包涵体，肝细胞内有大量自噬溶酶体。免疫电子显微镜检查包涵体呈角蛋白8/18和泛素阳性。在包裹体附近或包裹体内的自噬空泡中发现角蛋白8/18或泛素的金颗粒。角蛋白8过表达可加速MDB的形成，角蛋白8转基因小鼠是研究MDB形成的有用工具。自噬显然参与了MDB成分的消除。操纵自噬可能是各种包含性相关疾病的一种可能的治疗策略。
Several human liver diseases are associated with formation of hepatocyte Mallory-Denk bodies (MDB) composed of keratins and ubiquitin. Similar inclusions are found in various other diseases, neurodegenerative and muscle disorders. However, the mechanisms of MDB formation have been unclear. Autophagy is a degradation process of intracellular proteins and organelles. In the present study we examined the association of autophagy with the formation of MDB. We fed wild-type and keratin 8-transgenic mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet for 9 days. The livers were analyzed by immunohistochemistry and conventional and immune electron microscopy. Short-term DDC feeding induced MDB in keratin 8-transgenic but not in nontransgenic mouse livers. Electron microscopy revealed inclusions composed of electron-dense materials and filaments in hepatocyte cytoplasm and many autophagolysosomes in hepatocytes. Inclusions were positive for keratin 8/18 and ubiquitin examined by immunoelectron microscopy. Gold particles for keratin 8/18 or ubiquitin were found in the autophagic vacuoles near or in the inclusions. Keratin 8 overexpression accelerates MDB formation, and the keratin 8-transgenic mouse is a useful tool for the study of MDB formation. Autophagy apparently participates in the elimination of components of MDB. Manipulation of autophagy may be a possible therapeutic strategy for various inclusion-associated diseases.