期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：E4972-E4980
DOI：10.1073/pnas.1418954111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceProduction of functional sperm and eggs requires a complex process called meiosis. Meiosis in mouse and human eggs pauses at a stage called metaphase II (MII) arrest until fertilization by sperm. After fertilization, eggs released from MII arrest complete meiosis and develop into new individuals. In analyzing the female infertility of genetically altered mice, we discovered that excess cholesterol can trick mouse eggs into behaving as though they were fertilized (released from arrest), thus disrupting the normal synchrony between fertilization and completion of meiosis and rendering them dysfunctional. These findings suggest that abnormal cholesterol metabolism may contribute to some forms of human female infertility. The HDL receptor scavenger receptor, class B type I (SR-BI) controls the structure and fate of plasma HDL. Female SR-BI KO mice are infertile, apparently because of their abnormal cholesterol-enriched HDL particles. We examined the growth and meiotic progression of SR-BI KO oocytes and found that they underwent normal germinal vesicle breakdown; however, SR-BI KO eggs, which had accumulated excess cholesterol in vivo, spontaneously activated, and they escaped metaphase II (MII) arrest and progressed to pronuclear, MIII, and anaphase/telophase III stages. Eggs from fertile WT mice were activated when loaded in vitro with excess cholesterol by a cholesterol/methyl-{beta}-cyclodextrin complex, phenocopying SR-BI KO oocytes. In vitro cholesterol loading of eggs induced reduction in maturation promoting factor and MAPK activities, elevation of intracellular calcium, extrusion of a second polar body, and progression to meiotic stages beyond MII. These results suggest that the infertility of SR-BI KO females is caused, at least in part, by excess cholesterol in eggs inducing premature activation and that cholesterol can activate WT mouse eggs to escape from MII arrest. Analysis of SR-BI KO female infertility raises the possibility that abnormalities in cholesterol metabolism might underlie some cases of human female infertility of unknown etiology.
