Aberrant intracellular cholesterol transport disrupts pituitary and ovarian function.
Cholesterol is imported and processed to provide substrate for ovarian steroidogenesis. The Niemann Pick type C-1 gene codes for a glycoprotein that processes low-density lipoproteinimported cholesterol. Mutation of this gene causes marked impairment of export of low-density lipoprotein-derived cholesterol from endosomes, and consequent lysosomal accumulation of the sterol. The BALB/c npc(nih-/-) mouse line, bearing spontaneous mutation of the NPC-1 gene, provides a model for investigation of aberrant endosomal cholesterol transfer in the ovary. Female homozygote mutant mice are infertile, with underdeveloped ovarian follicles, reduced steroidogenesis, no ovulation, and no corpora lutea. Mutant ovaries transplanted under wild-type kidney capsules display both ovulation and formation of corpora lutea. Gonadotropin treatment induces ovulation and restores expression of steroidogenic proteins. Pituitary glands of mutants are hypoplastic, and prolactin expression is dramatically reduced compared with wild-type mice. Both long and short splice variants of the dopamine-D2 receptors are overexpressed in the pituitary of BALB/c npc(nih-/-) mice. Chronic treatment of mutant mice with 17beta-estradiol restores pituitary volume, prolactin expression, and folliculogenetic capability. We conclude that inactivating mutation of Niemann Pick C-1 perturbs the hypothalamic-pituitary-ovarian feedback loop. Reduced estrogens attenuate prolactin expression and alter gonadotropin secretion patterns and interfere with normal ovarian follicular development and ovulation.
Gévry
Nicolas Y
NY
Centre de Recherche en Reproduction Animale, Faculté de Médécine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 7C6.
Lopes
Flavia L
FL
Ledoux
Sandra
S
Murphy
Bruce D
BD
D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D003338:Corpus Luteum / Q000002:abnormalities / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006062:Gonadotropins / Q000494:pharmacology; D006720:Homozygote; D007247:Infertility, Female / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D010053:Ovary / Q000378:metabolism* / Q000503:physiopathology / Q000637:transplantation; D010060:Ovulation / Q000187:drug effects / Q000235:genetics; D010902:Pituitary Gland / Q000378:metabolism* / Q000503:physiopathology; D011388:Prolactin / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D019737:Transplants
D006062:Gonadotropins; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D004958:Estradiol; D011388:Prolactin; D002784:Cholesterol