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Effects of Hepatic Expression of the High-Density Lipoprotein Receptor SR-BI on Lipoprotein Metabolism and Female Fertility

Department of Biology, Massachusetts Institute of Technology (A.Y., S.L.K., M.K.), Cambridge, Massachusetts 02139; Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica (M.G.M., L.A., S.Z., A.R.), Santiago 833-0024, Chile; and Biopharmaceuticals Center of Excellence for Drug Discovery, GlaxoSmithKline (M.H.D., K.F.K.), King of Prussia, Pennsylvania 19406

Address all correspondence and requests for reprints to: Dr. Monty Krieger, Department of Biology, Massachusetts Institute of Technology, Room 68-483, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139. E-mail: krieger{at}mit.edu.

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.

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