TY - JOUR
T1 - Female infertility due to anovulation and defective steroidogenesis in NPC2 deficient mice
AU - Busso, D.
AU - Oñate-Alvarado, M. J.
AU - Balboa, E.
AU - Zanlungo, S.
AU - Moreno, R. D.
PY - 2010/2/5
Y1 - 2010/2/5
N2 - Niemann Pick C2 (NPC2) and NPC1 proteins function cooperatively to catalyze cholesterol efflux from lysosomes. NPC1 is expressed in ovarian cells and female NPC1 mice are infertile. This work addressed for the first time the localization and function of murine NPC2 protein in the ovary. Ovarian NPC2 was localized to theca and luteal cells, which use cholesterol as a substrate to produce estradiol and progesterone, respectively. NPC2 deficient (NPC2-/-) females had abnormal estrous cycles and were infertile, with normal folliculogenesis until the antral stage, but a complete absence of corpora lutea and many zonae pellucidae remnants, indicative of anovulation. Serum estradiol was reduced and ovarian cholesterol was accumulated in NPC2-/- mice, suggesting a defect in cholesterol export from intracellular stores. After superovulation, NPC2-/- mice ovulated less eggs than their wild type littermates, showed ovaries with less corpora lutea and numerous unruptured follicles, and lower serum progesterone concentration. Together, these results suggest that NPC2 participates in the traffic of ovarian cholesterol required to provide the substrate for steroid synthesis and support follicle maturation, ovulation and luteinization.
AB - Niemann Pick C2 (NPC2) and NPC1 proteins function cooperatively to catalyze cholesterol efflux from lysosomes. NPC1 is expressed in ovarian cells and female NPC1 mice are infertile. This work addressed for the first time the localization and function of murine NPC2 protein in the ovary. Ovarian NPC2 was localized to theca and luteal cells, which use cholesterol as a substrate to produce estradiol and progesterone, respectively. NPC2 deficient (NPC2-/-) females had abnormal estrous cycles and were infertile, with normal folliculogenesis until the antral stage, but a complete absence of corpora lutea and many zonae pellucidae remnants, indicative of anovulation. Serum estradiol was reduced and ovarian cholesterol was accumulated in NPC2-/- mice, suggesting a defect in cholesterol export from intracellular stores. After superovulation, NPC2-/- mice ovulated less eggs than their wild type littermates, showed ovaries with less corpora lutea and numerous unruptured follicles, and lower serum progesterone concentration. Together, these results suggest that NPC2 participates in the traffic of ovarian cholesterol required to provide the substrate for steroid synthesis and support follicle maturation, ovulation and luteinization.
KW - Cholesterol
KW - Female fertility
KW - NPC2
KW - Ovary
KW - Ovulation
KW - Steroids
UR - http://www.scopus.com/inward/record.url?scp=71849085133&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2009.10.011
DO - 10.1016/j.mce.2009.10.011
M3 - Article
C2 - 19883728
AN - SCOPUS:71849085133
SN - 0303-7207
VL - 315
SP - 299
EP - 307
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -