THE REGULATION OF FIBRINOGEN PRODUCTION INVOLVES AT LEAST ONE OTHER HEPATOCYTE GENE

It is currently thought that glucocorticosteriods have a direct effect on the transcription of the alpha, beta and gamma fibrinogen genes. However, our studies indicate that while corticosteriods play a role in fibrinogen production, this role is not due to transcriptional activation via glucocorticosteriod receptors. In initial experiments, we compared the levels of fibrinogen mRNA in hepatocytes isolated from hypophysectomized rats to those from control animals. The levels of mRNA in hypophysectomized rats, which produce little ACTH or corticosteriods, were significantly higher than the levels in control animals. Albumin mRNA levels were unaffected by hypophysectomy. These results are in opposition to those which we had anticipated. Based on previously published data, we had thought that physiologic deprivation of corticosteriods would lead to decreased levels of fibrinogen. We propose that these results are related to the negative feedback that corticosteroids have on Hepatocyte Stimulating Factor (HSF) production through a tightly controlled feedback circuit. To investigate the role of corticosteriods in fibrinogen gene regulation, we have conducted experiments with primary hepatocytes in culture and rat FAZA cells (continuous hepatoma cell line). There is a 4 to 5 fold increase in fibrinogen production when these cells are treated with HSF but no change when these cells are treated with dexamethasone alone. However, there is a marked additional increase in the production of fibrinogen with the combination of dexamethasone and HSF. Data gathered through kinetic analysis of this synergistic interaction suggest that the maximum response to HSF requires another gene product whose production is responsive to dexamethasone. Detailed analysis of the rate of transcription of thegamma fibrinogen gene, its processing and mRNA turnover suggests a specific role for this gene product in regulating fibrinogen synthesis. Characterization of this gene product will lead to greater understanding of the regulation of the Acute Phase Reactants.