Probucol therapy overcomes the reproductive defect in CTP: phosphocholine cytidylyltransferase β2 knockout mice

Abstract

The synthesis of phosphatidylcholine (PtdCho), the major phospholipid in mammalian cells, is regulated by the CTP:phosphocholine cytidylyltransferase (CCT). Loss of the CCTβ2 isoform expression in mice results in gonadal dysfunction. CCTβ2 −/− 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 CCTβ2 −/− 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 CCTβ2 −/− 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 of cellular phospholipid.

An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome

“…Choline and phosphocholine are precursors for phosphatidylcholines, which are key components of biological membranes. Disruption to the phosphatidylcholine-producing pathway in female transgenic mice results in compromised ovarian follicle development and oocyte maturation (51). The observed decrease in these choline metabolites in our study may be a causal factor for lack of development past the one-cell stage.…”

Phosphatidylcholine and the CDP–choline cycle

“…The CCTβ knockout mouse displays premature gonadal senescence and CCTβ is expressed at its highest levels in the gonads and brain [57]. Interestingly, the CCTβ phenotype is prevented by probucol therapy [125]. Probucol is a cholesterol-lowering drug that also rescues the gonadal dysfunction in high density lipoprotein (HDL)-receptor knockout mice [126].…”

Gene knockouts that affect male fertility: novel targets for contraception

“…Phosphotidylcholine is an important part of biological membranes, and its synthesis is partially regulated by CTP:Phosphocholine cytidylyltransferase (CCT), which includes the isoform of interest CCTβ2. Loss of the more crucial isoform α causes lethality in early embryogenesis while deletion of the β2 isoform harbors significant infertility (37). The homozygous knockout displays a disorganized ovarian structure and failure of normal follicle growth (37).…”

“…Loss of the more crucial isoform α causes lethality in early embryogenesis while deletion of the β2 isoform harbors significant infertility (37). The homozygous knockout displays a disorganized ovarian structure and failure of normal follicle growth (37). Additional phenotypes include fewer junctions between granulosa cells, decreased penetration of granulosa microvilli through the zona pellucida, distorted Golgi apparatus, and decreased rough endoplasmic reticulum with an increase in free ribosomes (37).…”

“…There has been debate over whether Lfng is truly a target gene for infertility, as a recent study reported that all female knockout mice were interfile, only to publish later that some were in fact fertile. Lfng seems to be associated with infertility, although it may not be associated with complete sterility (37). Lfng deletion causes follicle and meiotic maturation defects (41,42).…”