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.

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

“…1 ). This is in contrast to work previously published by Yesilaltay et al ( 69 ), which found overexpression of LCAT in mice on a Scarab ( Ϫ / Ϫ ) background was not able to normalize the FC/TC ratio. The differences between our results and theirs are likely due to the much greater increase in LCAT expression in our mice compared with the previous study ( 31,70 ).…”

Lipids and oocyte developmental competence: the role of fatty acids and β-oxidation

“…Studies in the mouse demonstrate the importance of HDL integrity for oocyte competence; as knockout mice lacking the HDL receptor scavenger receptor class B, member 1 (SRBI) are infertile due to fertilised oocytes arresting before the morula stage (Miettinen et al 2001). These mice have abnormally large circulating HDL particles and, interestingly, restoration of SRBI expression in the liver alone is sufficient to normalise HDL particle size and restore fertility (Yesilaltay et al 2006). Increased HDL in human follicular fluid was associated with low embryo fragmentation (Browne et al 2008(Browne et al , 2009, suggesting that HDL components play a cytoprotective role for the oocyte.…”

Scavenger receptor-B1 and luteal function in mice

“…The observation that nonviable oocytes are produced has led to the implication that the ovulatory process itself is disrupted in some way ( 11,12 ). Although mechanisms remain unclear, it is intriguing that targeted overexpression of SCARB1 in the liver rescues fertility of SCARB1 null mice to nearly the levels found in wild-type mice ( 13 ). In addition, fertility was rescued by treatment with Probucol, a drug that lowers circulating cholesterol independent of SCARB1 ( 14 ).…”