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This version published online on January 12, 2006
Endocrinology, doi:10.1210/en.2005-1286
A more recent version of this article appeared on April 1, 2006
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*CHOLESTEROL

Submitted on October 11, 2005
Accepted on January 4, 2006

EFFECTS OF HEPATIC EXPRESSION OF THE HDL-RECEPTOR SR-BI ON LIPOPROTEIN METABOLISM AND FEMALE FERTILITY

Ayce Yesilaltay, María Gabriela Morales, Ludwig Amigo, Silvana Zanlungo, Attilio Rigotti, Sharon L. Karackattu, Mary H. Donahee, Karen F. Kozarsky, and Monty Krieger*

Department of Biology, Massachusetts Institute of Technology, Room 68-483, 77 Massachusetts Avenue, Cambridge, MA 02139; Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta 367, Santiago, Chile; Biopharmaceuticals CEDD, GlaxoSmithKline, King of Prussia, PA 19406

* To whom correspondence should be addressed. E-mail: krieger{at}mit.edu.

The etiology of human female infertility is often uncertain. Sterility of 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) that is unable to bind to and mediate lipid transfer from wild-type HDL normally, but retains virtually normal lipid transport activities with LDL. 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, while ~7-40-fold overexpression dramatically lowered plasma total cholesterol and increased biliary cholesterol secretion. On the other hand, SR-BI-RR overexpression had little effect on SR-BI (+/+) mice, but in SR-BI (-/-) mice 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.
Key words: high density lipoprotein receptor • fertility • cholesterol




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