Betamethasone activation of CTP:cholinephosphate cytidylyltransferase is mediated by fatty acids.
The purpose of the present study was to determine the mechanisms by which glucocorticoids increase the activity of CTP:cholinephosphate cytidylyltransferase, a key enzyme required for the synthesis of surfactant phosphatidylcholine. Lung cytidylyltransferase exists as an inactive, light form low in lipids (L-form) and an active, heavy form high in lipid content (H-form). In vitro, fatty acids stimulate and aggregate the inactive L-form to the active H-form. In vivo, betamethasone increases the amount of H-form while decreasing the amount of L-form in fetal lung. There is also a coordinate increase in total free fatty acids in the H-form. In the present study, we used gas chromatography-mass spectrometry to measure the fatty acid species associated with the H-forms in fetal rat lung after the mothers were treated with betamethasone (1 mg/kg). In vivo, betamethasone increased the total amount of free fatty acids associated with the H-form by 62%. Further, the hormone selectively increased the mass of myristic and oleic acids in H-form by 52 and 82%, respectively. However, betamethasone produced the greatest increase in the amount of H-form linoleic acid, which increased fourfold relative to control. In vitro, each of the fatty acids increased L-form activity in a dose-dependent manner; however, linoleic acid was the most potent. Linoleic and oleic acids also effectively increased L-form aggregations. These observations suggest that in vivo glucocorticoids elevate the level of specific fatty acids which convert cytidylyltransferase to the active form.
Department of Internal Medicine, Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242.
R K
RK
Mallampalli
R G
RG
Salome
C H
CH
Li
M
M
VanRollins
G W
GW
Hunninghake
D000818:Animals; D001623:Betamethasone / Q000494:pharmacology*; D019916:Choline-Phosphate Cytidylyltransferase; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008168:Lung / Q000196:embryology / Q000201:enzymology*; D008431:Maternal-Fetal Exchange; D009713:Nucleotidyltransferases / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D011663:Pulmonary Surfactants / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; D011663:Pulmonary Surfactants; D014284:Triiodothyronine; D011374:Progesterone; D004958:Estradiol; D001623:Betamethasone; D009713:Nucleotidyltransferases; D019916:Choline-Phosphate Cytidylyltransferase