Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology

Abstract

The high density lipoprotein (HDL) receptor SR-BI (scavenger receptor class B type I) mediates the selective uptake of plasma HDL cholesterol by the liver and steroidogenic tissues. As a consequence, SR-BI can inf luence plasma HDL cholesterol levels, HDL structure, biliary cholesterol concentrations, and the uptake, storage, and utilization of cholesterol by steroid hormone-producing cells. Here we used homozygous null SR-BI knockout mice to show that SR-BI is required for maintaining normal biliary cholesterol levels, oocyte development, and female fertility. We also used SR-BI͞apolipoprotein E double homozygous knockout mice to show that SR-BI can protect against early-onset atherosclerosis. Although the mechanisms underlying the effects of SR-BI loss on reproduction and atherosclerosis have not been established, potential causes include changes in (i) plasma lipoprotein levels and͞or structure, (ii) cholesterol f lux into or out of peripheral tissues (ovary, aortic wall), and (iii) reverse cholesterol transport, as indicated by the significant reduction of gallbladder bile cholesterol levels in SR-BI and SR-BI͞apolipoprotein E double knockout mice relative to controls. If SR-BI has similar activities in humans, it may become an attractive target for therapeutic intervention in a variety of diseases.High density lipoprotein (HDL)-cholesterol levels are inversely proportional to the risk for atherosclerosis (1). This may be due partly to ''reverse cholesterol transport'' (RCT), in which HDL is proposed to remove excess cholesterol from cells, including those in the artery wall (2-7), and transport it, either indirectly or directly (8, 9), to the liver for biliary secretion. HDL also can deliver cholesterol directly to steroidogenic tissues (adrenal gland, testis, ovary) for storage in cytoplasmic cholesteryl ester droplets and for steroid hormone synthesis (10-12). Thus, HDL may influence a variety of endocrine functions, including reproduction. A key mechanism of receptor-mediated direct delivery of HDL cholesteryl esters to the liver and steroidogenic tissues is selective cholesterol uptake, in which only the cholesteryl esters of the HDL particles (not the apolipoproteins) are transferred efficiently to cells (8, 9).The class B type I scavenger receptor, SR-BI, is a cellsurface HDL receptor that mediates selective lipid uptake (13-21; reviewed in refs. 22 and 23). It is most highly expressed in the liver and steroidogenic tissues, in which its activity is regulated by trophic hormones (13, 24-31). As a consequence, SR-BI is a key regulator of HDL cholesterol levels (17-21) and adrenal cholesterol stores (18). The finding that hepatic SR-BI overexpression leads to significant increases in biliary cholesterol content (17, 32) is consistent with gene-targeting studies (18,19) that suggest an important role for SR-BI in RCT. In addition to HDL, SR-BI can bind other ligands, including lipoproteins [LDL, modified LDL, very low density lipoprotein (VLDL)] and apolipoproteins (33-37), and can mediate efflux...

Trophoblast‐like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins

“…Evidence is accumulating that cholesterol must be considered as an essential agent in embryonic development. Histochemical analysis of ovaries from superovulated females showed reduced oil red O staining of lipids in the ovarian copora lutea of SR-BI knock out relative to those of wild-type animals suggesting reduced CE storage as a source for steroid hormone production [61]. Also plasma progesterone levels between pseudopregnant controls and knock out females 6 days after mating were slightly although not significantly impaired.…”

“…Also plasma progesterone levels between pseudopregnant controls and knock out females 6 days after mating were slightly although not significantly impaired. Finally, the majority of embryos from SR-BI knock out females at harvesting showed abnormal, nonrefractile morphology of oocytes and embryos [61] similar to wild-type females that had been treated with cholesterol-binding drugs that can perturb membrane structure. Female mice with a targeted null mutation of the SR-BI gene are infertile [61], a fact underscoring the importance of the SR-BI pathway during embryonic development.…”

“…Finally, the majority of embryos from SR-BI knock out females at harvesting showed abnormal, nonrefractile morphology of oocytes and embryos [61] similar to wild-type females that had been treated with cholesterol-binding drugs that can perturb membrane structure. Female mice with a targeted null mutation of the SR-BI gene are infertile [61], a fact underscoring the importance of the SR-BI pathway during embryonic development. As SR-BI is expressed on the maternal-fetal interface [16], this could indicate defective cholesterol/CE-supply to the growing embryo.…”

Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

“…This may also contribute to the decrease in the plasma corticosterone level in SR-BI-deficient mice. Importantly, Trigatti et al (27) have shown that female SR-BIdeficient mice are infertile, probably because of a similarly impaired steroidogenesis in the ovaries. Given the fact that SR-BI-deficient mice have very high circulating levels of ACTH, a potent activator of adrenal cortex glucocorticoid production (28), and a concomitant increase in adrenal weight under fasting conditions, it is suggested that SR-BI-deficient mice are unable to respond adequately to physiological stress impulses, as they suffer from adrenal glucocorticoid insufficiency.…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…Although the selective deletion of ABCA1 in macrophages (Brunham et al, 2009) and the overexpression of ABCG1 (Burgess et al, 2008) did not significantly modulate the development of atherosclerotic plaques, simultaneous deficiency in both ABCA1 and ABCG1 promoted atherosclerosis in mice (Yvan-Charvet et al, 2007). In addition to ABCA1 and ABCG1, SR-BI, another type B scavenger receptor, protects against atherosclerosis when expressed in macrophages by stimulating cholesterol efflux, whereas genetically suppressing SR-BI activity in ApoE-deficient mice dramatically accelerates the onset of atherosclerosis (Trigatti et al, 1999). The SR-BI-mediated reverse cholesterol transport process demonstrated in macrophages was confirmed in vivo using ABCA1/SR-BI double knockout mice (Zhao et al, 2011).…”