Yuan Q X, Marceau N, French B A, Fu P, French S W
Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA 90509, USA.
Exp Mol Pathol. 1995 Aug;63(1):63-76. doi: 10.1006/exmp.1995.1031.
Perturbations in keratin intermediate filament organization and Mallory body (MB) formation are associated with alcoholic hepatitis. Inducible heat shock proteins (HSPs) are expressed in a variety of liver diseases including alcoholic liver disease. Therefore, we investigated whether heat shock protein induction can lead to MB formation. Mice were primed by a 5-month feeding of griseofulvin (GF) or diethyl 1,4-dehydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) followed by drug withdrawal for 1 month. The animals were then subjected to an in vivo heat shock treatment or sham heat treatment. Liver morphology, HSP expression, liver regeneration (PCNA-labeled nuclei), and MB formation were monitored during a 7-day posttreatment period. Numerous MBs developed in the livers of mice exposed to GF or DDC for 5 months, but very few small MBs remained after 1-month withdrawal of either drug. No MBs were found at Day 1 post heat shock, whereas numerous MBs were observed at Day 7. The frequency of PCNA-labeled nuclei increased during the same period. At Day 1 posttreatment, a variable liver centrilobular necrosis was observed accompanied by a prominent increase in HSP-25 and HSP70 expression, but HSP-90 expression was not increased. In drug-primed mouse liver, a heat shock treatment induces the expression of specific HSPs prior to the formation of MBs, indicating that HSP expression may play a role in the pathogenesis of MB formation. We speculate that this role is through the protein unfolding function of HSP, which leads to the aggregation of the cytokeratins to form MBs as well as to polyubiquitin binding to these proteins in a manner analogous to amyloid formation.
角蛋白中间丝组织的紊乱和马洛里小体（MB）的形成与酒精性肝炎相关。可诱导的热休克蛋白（HSPs）在包括酒精性肝病在内的多种肝脏疾病中表达。因此，我们研究了热休克蛋白的诱导是否会导致MB的形成。通过给小鼠喂食5个月的灰黄霉素（GF）或1,4 - 脱氢 - 2,4,6 - 三甲基 - 3,5 - 吡啶二羧酸二乙酯（DDC）进行预处理，然后停药1个月。随后对动物进行体内热休克处理或假热休克处理。在处理后的7天内监测肝脏形态、HSP表达、肝脏再生（PCNA标记的细胞核）和MB形成。暴露于GF或DDC 5个月的小鼠肝脏中出现了大量的MB，但在停用任何一种药物1个月后，只剩下很少的小MB。热休克后第1天未发现MB，而在第7天观察到大量MB。同期PCNA标记的细胞核频率增加。处理后第1天，观察到肝小叶中央区出现不同程度的坏死，同时HSP - 25和HSP70表达显著增加，但HSP - 90表达未增加。在药物预处理的小鼠肝脏中，热休克处理在MB形成之前诱导特定HSP的表达，表明HSP表达可能在MB形成的发病机制中起作用。我们推测这种作用是通过HSP的蛋白质解折叠功能实现的，该功能导致细胞角蛋白聚集形成MB，以及多聚泛素以类似于淀粉样蛋白形成的方式与这些蛋白质结合。
