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KMID : 0602619980040040381
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Korean Journal of Hepatology
1998 Volume.4 No. 4 p.381 ~ p.392
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The Relevance of Degree of Liver Fibrosis, Ito cell, and PKC Activity in Hepatic Fibrogenesis
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Abstract
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Background/Aims Hepatic fibrosis in rat induced by thioacetamide shares similar morphological and biochemical characteristics with human liver cirrhosis. Thioacetamide (TAA) initially induces accumulation of collagen in Disse space and eventually leads to macro- and micronodular cirrhosis. Ito cell was believed to play a main role in hepatic fibrosis. And its activity was known to be regulated by the expression of various genes. But little has been discovered about the upstream signal transduction pathway of these genes in hepatic fibrosis. The expression of genes related to Ito cell activity was regulated by many transcription factors, the activity of which was regulated by protein kinase C(PKC) isoforms. So it is supposed that PKC could be associated with fibrosis in liver. Methods : We investigated the correlation of PKC isoforms and Ito cell activity in the course of hepatic fibrosis using TAA induced rat liver cirrhosis model. We used six week-old male rats, and administered 0.03% TAA in drinking water. The animals were sacrificed at 9, 20, and 30 weeks after TAA administration. The degree of hepatic fibrosis was evaluated by measuring the total amount of collagen. a -SMA immunohistochemical staining of liver tissue was done to determine the Ito cell activity. The expression pattern of PKC isoforms was investigated by Western blotting. Results : In TAA-treaed group, collagen content and Ito cell activity did not increase until 30 weeks and 20 weeks of treatment, respectively, while in control group collagen content and Ito cell activity were not detected. Collagen content showed linear correlation with Ito cell activity. This implied that the proliferation of activated Ito cells was prior to the increase of collagen content. In view of expression pattern of PKC isoforms, PKC a showed no difference in TAA-treated group and control group. In TAA-treated group, PKC Q 1 exhibited increased level of expression in both particulate and cytosolic forms at 9 weeks, while PKC 8 and PKC e showed striking shift to particulated foiiu. After 20 weeks, all of the PKC I31, 8 , and e degenerated and showed remarkably decreased level of expression. This suggested PKC .a had no relation to hepatic fibrosis, while PKC b´ 1, 8 , and e , showing activity at 9 weeks, were related to fibrosis of liver. In response to fibrogenic factors, molecules engaged in intracellular signal transduction pathway like PKC a 1, 8 , and e , begin to change prior to the increase of Ito cell activity, morphologic changes and alterations of collagen content. Conclusion : Our results strongly suggest that the activity of PKC isofoiInis play an important role in early step of hepatic fibrosis, while accompanying Ito cell activity do in later step.
(Korean J Hepatol 19984381?392)
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