GLUCOCORTICOID AND CAMP INCREASE FATTY-ACID SYNTHETASE MESSENGER-RNA IN HUMAN FETAL LUNG EXPLANTS

During late fetal development, synthesis of surfactant phospholipid re quires a large supply of fatty acid precursor. Fatty acid synthetase i s a regulatory enzyme for de novo fatty acid synthesis in lung as well as other lipogenic tissues. In this study, we report hormonal inducti on of FAS mRNA in human fetal lung explants (16-23 week gestation) cul tured up to 7 days in Waymouth's medium (no serum) supplemented with d examethasone (Dex, 10 nM) or agents that increase cAMP (8-Br-cAMP, 0.1 mM; isobutylmethylxanthine, 0.1 mM; forskolin, 0.01 mM; PGE(1), 0.01 mM). Exposure of explants to Dex or cAMP agents increased FAS mRNA con tent by 6 h and maximal stimulation occurred at 72 h for Dex (approx. 3-fold increase) and 24 h for cAMP (approx. 2-fold increase). In the p resence of both Dex and cAMP there was a synergistic increase in FAS m RNA content at all times (approx. ii-fold increase at 72 h). Induction of FAS mRNA was specific for steroids with glucocorticoid activity, r eversible on removal of hormone, and was half-maximal at 2-3 nM Dex co nsistent with receptor mediation. Actinomycin D blocked induction by D ex but not by cAMP suggesting a transcriptional effect by glucocortico id but not by cAMP. T-3, which increases phosphatidylcholine synthesis , did not induce FAS mRNA. The findings indicate that both glucocortic oid and cAMP increase FAS gene expression consistent with an important role for FAS in regulating the supply of fatty acid for surfactant ph ospholipid synthesis.