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.
Mallampalli
R K
RK
Department of Internal Medicine, Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242.
Salome
R G
RG
Li
C H
CH
VanRollins
M
M
Hunninghake
G W
GW
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