Probucol therapy overcomes the reproductive defect in CTP: phosphocholine cytidylyltransferase beta2 knockout mice.
The synthesis of phosphatidylcholine (PtdCho), the major phospholipid in mammalian cells, is regulated by the CTP:phosphocholine cytidylyltransferase (CCT). Loss of the CCTbeta2 isoform expression in mice results in gonadal dysfunction. CCTbeta2(-/-) females exhibit ovarian tissue disorganization with progressive loss of follicle formation and oocyte maturation. Ultrastructure revealed a disrupted association between ova and granulosa cells and disorganized Golgi apparati in oocytes of CCTbeta2(-/-) mice. Probucol is a cholesterol-lowering agent that stimulates the uptake and retention of lipids carried by lipoproteins in peripheral tissues. Probucol therapy significantly lowered both serum cholesterol and PtdCho levels. Probucol therapy increased fertility in the CCTbeta2(-/-) females 100%, although it did not completely correct the phenotype, the morphological abnormalities in the knockout ovaries or itself stimulate CCT activity directly. These data indicated that a deficiency in de novo PtdCho synthesis could be complemented by altering the metabolism of serum lipoproteins, an alternative source for cellular phospholipid.
Gunter
Christopher
C
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
Frank
Matthew
M
Tian
Yong
Y
Murti
K Gopal
KG
Rehg
Jerold E
JE
Jackowski
Suzanne
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D019916:Choline-Phosphate Cytidylyltransferase / Q000172:deficiency*; D004958:Estradiol / Q000097:blood; D005260:Female; D005298:Fertility / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006058:Gonadal Disorders / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D010767:Phosphorylcholine / Q000097:blood; D011341:Probucol / Q000494:pharmacology / Q000627:therapeutic use*; D011374:Progesterone / Q000097:blood; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism
D000924:Anticholesteremic Agents; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D010767:Phosphorylcholine; D011374:Progesterone; D004958:Estradiol; D002784:Cholesterol; C476147:CTP phosphocholine cytidylyltransferase, beta isoform, mouse; D019916:Choline-Phosphate Cytidylyltransferase; D011341:Probucol