title: Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility.
abstract: The etiology of human female infertility is often uncertain. The sterility of high-density lipoprotein (HDL) receptor-negative (SR-BI(-/-)) female mice suggests a link between female infertility and abnormal lipoprotein metabolism. SR-BI(-/-) mice exhibit elevated plasma total cholesterol [with normal-sized and abnormally large HDL and high unesterified to total plasma cholesterol (UC:TC) ratio]. We explored the influence of hepatic SR-BI on female fertility by inducing hepatic SR-BI expression in SR-BI(-/-) animals by adenovirus transduction or stable transgenesis. For transgenes, we used both wild-type SR-BI and a double-point mutant, Q402R/Q418R (SR-BI-RR), which is unable to bind to and mediate lipid transfer from wild-type HDL normally, but retains virtually normal lipid transport activities with low-density lipoprotein. Essentially wild-type levels of hepatic SR-BI expression in SR-BI(-/-) mice restored to nearly normal the HDL size distribution and plasma UC:TC ratio, whereas approximately 7- to 40-fold overexpression dramatically lowered plasma TC and increased biliary cholesterol secretion. In contrast, SR-BI-RR overexpression had little effect on SR-BI(+/+) mice, but in SR-BI(-/-) mice, it substantially reduced levels of abnormally large HDL and normalized the UC:TC ratio. In all cases, hepatic transgenic expression restored female fertility. Overexpression in SR-BI(-/-) mice of lecithin:cholesterol acyl transferase, which esterifies plasma HDL cholesterol, did not normalize the UC:TC ratio, probably because the abnormal HDL was a poor substrate, and did not restore fertility. Thus, hepatic SR-BI-mediated lipoprotein metabolism influences murine female fertility, raising the possibility that dyslipidemia might contribute to human female infertility and that targeting lipoprotein metabolism might complement current assisted reproductive technologies.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, USA.
authors.forename: Ayce
authors.initials: A
authors.lastname: Yesilaltay
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.forename: Ludwig
authors.initials: L
authors.lastname: Amigo
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Karackattu
authors.forename: Mary H
authors.initials: MH
authors.lastname: Donahee
authors.forename: Karen F
authors.initials: KF
authors.lastname: Kozarsky
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005298:Fertility; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000502:physiology*
chemical_list: D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase