GLUCOCORTICOIDS INCREASE FATTY-ACID SYNTHASE MESSENGER-RNA STABILITY IN FETAL-RAT LUNG

Fatty-acid synthase (FAS) is a critical enzyme in surfactant biosynthe sis. In fetal lung, glucocorticoids increase synthesis of phosphatidyl choline, the principal lipid component of surfactant, and there is evi dence that this effect is mediated by increased expression of the FAS gene. Dexamethasone increases FAS activity, mass, mRNA content, and ra te of transcription in cultured explants of fetal rat lung. As previou s experiments with actinomycin D suggested that dexamethasone may also increase FAS mRNA content by a posttranscriptional mechanism, we exam ined the effect of the hormone on FAS mRNA stability. Explants of 19-d ay fetal rat lungs were cultured for 44 h with and without 100 nM dexa methasone. Some explants were harvested at that point, and others were cultured further with 60 mu M 5,6-dichlororibofuranosylbenzimidazole (DRB), an inhibitor of transcription. RNA was then extracted, and FAS mRNA levels were measured by Northern analysis. mRNA stability was ass essed by comparing the amount remaining after culture with DRB with th e initial level before addition of the inhibitor. The apparent half-li fe of FAS mRNA was 4 h in control explants cultured without hormone. F AS mRNA stability was increased 84% in the explants cultured with dexa methasone for 44 h and by 40% in those cultured with the hormone for 5 h. We conclude that glucocorticoids enhance expression of the FAS gen e in fetal lung by increasing mRNA stability in addition to stimulatin g transcription.