Glucocorticoids suppress formation of collagen by the hepatocyte. Studies in primary monolayer cultures of parenchymal cells prepared from adult rat liver.
We have established previously that the adult rat hepatocyte produces collagen under conditions of primary monolayer culture or under pathologic conditions in vivo. During the initial 3 days of incubation of hepatocytes in serum-free culture medium, collagen synthesis represented only 0.01%-0.05% of the synthesis of noncollagen proteins. Thereafter, rates of collagen synthesis rose dramatically, and after 9 days of incubation were increased an average tenfold in cultures derived from normal hepatocytes and 30-fold in cultures derived from regenerated liver. The spontaneous increase in the rates of collagen synthesis was almost completely blocked (94%) when cultures were incubated for 8 days in medium containing the synthetic glucocorticoid dexamethasone (10(-7) M). Dexamethasone was without effect on the synthesis of noncollagen proteins. Inhibition of collagen synthesis by dexamethasone exhibited a sigmoidal dose-response curve with 50% inhibition observed at a concentration of 10(-9) M. Collagen synthesis was diminished similarly by other glucocorticoids (hydrocortisone, methylprednisolone, triamcinolone, prednisone, all 10(-6) M) but not by other hormonal or nonhormonal steroids (progesterone, estradiol, testosterone, all 10(-5) M). We excluded increased collagen degradation as an explanation for these results by demonstrating that dexamethasone failed to increase the incorporation of radioactive proline into trichloroacetic acid-soluble radioactive hydroxyproline. Exposure of hepatocytes to dexamethasone during the first 48 h of incubation produced inhibition of collagen synthesis in 9-day-old cultures, even though washout studies with [3H]dexamethasone revealed negligible retention of the steroid by the cells. This observation suggests that among the initial, culture-adaptive responses of the hepatocyte are glucocorticoid-sensitive events that culminate in increased rates of collagen synthesis days later. We conclude that glucocorticoids may serve as natural suppressors of the potential of the hepatocyte to produce collagen.
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D005938:Glucocorticoids; D003907:Dexamethasone; D003094:Collagen; D006909:Hydroxyproline