Differential effect of micronodular and biliary cirrhosis on epidermal growth factor receptor expression in the rat.
Cirrhosis is characterized by fibrogenesis, hepatocyte necrosis and the formation of regenerative nodules. Modulation of the epidermal growth factor receptor is an early event during regeneration. We have recently demonstrated alterations in the epidermal growth factor receptor during the development of biliary cirrhosis. The aim of the present study was to compare epidermal growth factor receptor distribution, expression and binding in biliary cirrhosis to that occurring in micronodular cirrhosis induced by phenobarbital/CCl4 exposition. Biliary cirrhosis and micronodular cirrhosis had similar functional impairment as assessed by the aminopyrine breath test. Epidermal growth factor receptor binding capacity was reduced in both models (control vs micronodular cirrhosis vs biliary cirrhosis: (mean +/- 1 SD) 60 +/- 22 vs 16 +/- 12 vs 27 +/- 9 fmol/mg protein, p < 0.05), while the binding constant was increased in biliary cirrhosis only. The receptor mass in plasma membrane, determined by Western blotting, was not changed. Distribution of epidermal growth factor receptor was assessed immunohistochemically on tissue sections. In both models, cytoplasmic staining was decreased and basolateral plasma membrane labeling was maintained. Nuclear localization was found in biliary cirrhosis only. In conclusion, in both models, cirrhosis induces an alteration in the binding properties, but not in the number of epidermal growth factor receptors in the plasma membrane. The loss of cytoplasmic epidermal growth factor receptor could reflect alterations in expression and/or in intracellular trafficking. This is supported by the reduced mRNA steady state levels for epidermal growth factor receptor which were found in both models, presumably representing down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Oguey
D
D
Department of Clinical Pharmacology, University of Berne, Switzerland.
Reichen
J
J
Marti
U
U
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D066246:ErbB Receptors / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009994:Osmolar Concentration; D010634:Phenobarbital; D051381:Rats; D017207:Rats, Sprague-Dawley
D002251:Carbon Tetrachloride; D066246:ErbB Receptors; D010634:Phenobarbital