Pathological implications of cadherin zonation in mouse liver
Pathological implications of cadherin zonation in mouse liver
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DOI：
10.1007/s00018-015-1861-y
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发表时间：
2015-07-01
影响因子：
8
通讯作者：
Christ, Bruno
中科院分区：
文献类型：
--
作者：
Hempel, Madlen;Schmitz, Annika;Christ, Bruno
急性和慢性肝病都与肝实质的充分重建相关，导致功能障碍，因此这显然是上皮完整性破坏的原因或结果。因此，本研究的目的是研究粘附连接组分E-和N-钙粘蛋白的分布，这是组织凝聚力的重要决定因素。E-cadherin在门静脉周围肝细胞中表达，而在静脉周围肝细胞中不表达。与此相反，N-钙粘蛋白更丰富的静脉周围肝细胞。与此一致的是，β-连环蛋白，它通过α-连环蛋白将两种钙粘蛋白连接到肌动蛋白细胞骨架上，被普遍表达。在用对乙酰氨基酚或部分肝切除术治疗后的急性肝损伤中，钙粘蛋白的这种带状表达得以保留，但在慢性肝损伤中如非酒精性脂肪性肝炎（NASH）或α 1-抗胰蛋白酶缺乏症中被破坏。在对乙酰氨基酚诱导的肝损伤过程中，肝细胞增殖主要发生在受损的静脉周围和完整的门静脉周围实质之间的边界处，这表明门静脉周围肝细胞对肝再生的贡献很小。在NASH肝脏中，观察到卵圆细胞反应，表明大规模组织损伤与肝细胞增殖的严重损害一致。在肝实质中，代谢功能分布不均匀。例如，磷酸烯醇式丙酮酸羧激酶和E-钙粘蛋白的表达在门静脉周围肝细胞中重叠。因此，在急性损伤后的肝再生过程中，完整的门静脉周围实质可能维持必要的代谢支持，如葡萄糖供应或氨解毒。然而，在慢性挑战期间上皮完整性的破坏可能会增加对代谢性肝病如NASH的易感性，反之亦然。这可能表明肝脏中组织凝聚力和代谢功能的调节整合。
Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, beta-catenin, which links both cadherins via alpha-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or alpha 1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.