Jeong D H, Lee S J, Lee J H, Bae I H, Jeong K S, Jang J J, Lim I K, Kim M R, Lee M J, Lee Y S
College of Veterinary Medicine, Kyungpook National University, Daegue, Korea.
J Gastroenterol Hepatol. 2001 Jan;16(1):34-40. doi: 10.1046/j.1440-1746.2001.02364.x.
Protein kinase C (PKC) plays a key role in the alteration of signal transduction in the liver, which may contribute to the development of liver cirrhosis. The aim of the present study was to examine the subcellular redistribution of PKC isozymes in rat liver cirrhosis, which is induced by two different cirrhotic chemical agents, carbon tetrachloride (CCl4) and thioacetamide (TAA).
Thioacetamide and CCl4 were administered to rats for 8 and 30 weeks, respectively before rats were killed and autopsies performed at 9, 20 and 30 weeks later. The TAA induced a fibrotic pattern in the liver that differed from that produced by CCl4, notably in the formation of fibrous connective tissue and the proliferation of bile ductule cells. Cholangiofibrosis and clear-cell foci were also observed in TAA-treated rats at 30 weeks. Histological examination revealed that severe cirrhotic changes were present 9 weeks after the commencement of CCl4 treatment and 30 weeks after TAA treatment.
When the subcellular redistribution of PKC isozymes (PKCalpha, -beta1, -delta, and -epsilon) was examined, all the PKC isozymes in CCl4-treated rats were found to be translocated to the membrane fraction, which may mean PKC activation, and then downregulated by proteolytic degradation after 9 weeks of treatment, which coincided with peak cirrhotic changes. All rats treated with CCl4 recovered to the control level after 20 weeks of treatment. In the case of TAA-treated rats, PKC isozymes were translocated to the particulate fraction of the liver after 9 weeks of treatment and this persisted in most of the rats for the duration of the experiment.
From these results, it would appear that PKC translocation preceded morphologic changes, and that an altered subcellular distribution of the PKC isozyme may be associated with the response to liver damage and carcinogenesis.
蛋白激酶C（PKC）在肝脏信号转导改变中起关键作用，这可能促使肝硬化的发展。本研究旨在检测由两种不同的肝硬化化学试剂，即四氯化碳（CCl4）和硫代乙酰胺（TAA）诱导的大鼠肝硬化中PKC同工酶的亚细胞重新分布情况。
分别给大鼠施用硫代乙酰胺和CCl4 8周和30周，之后将大鼠处死，并在9周、20周和30周后进行尸检。TAA诱导的肝脏纤维化模式与CCl4诱导的不同，特别是在纤维结缔组织形成和胆小管细胞增殖方面。在TAA处理30周的大鼠中还观察到胆管纤维化和透明细胞灶。组织学检查显示，CCl4处理开始9周后以及TAA处理30周后出现严重的肝硬化变化。
当检测PKC同工酶（PKCalpha、-beta1、-delta和-epsilon）的亚细胞重新分布时，发现CCl4处理的大鼠中所有PKC同工酶都转位到膜部分，这可能意味着PKC激活，然后在处理9周后通过蛋白水解降解而下调，这与肝硬化变化的高峰期一致。所有接受CCl4处理的大鼠在处理20周后恢复到对照水平。在TAA处理的大鼠中，PKC同工酶在处理9周后转位到肝脏的颗粒部分，并且在大多数大鼠中在实验期间持续存在。
从这些结果来看，PKC转位似乎先于形态学变化，并且PKC同工酶亚细胞分布的改变可能与肝脏损伤反应和致癌作用有关。
