SR-BI is the main receptor for high density lipoproteins (HDL) and mediates the bidirectional transport of lipids, such as cholesterol and vitamin E, between these particles and cells. During early development, SR-BI is expressed in extraembryonic tissueScavenger Receptor Class B type I (SR-BI) is the main receptor for high density lipoproteins (HDL), and numerous studies have described its role in mediating the bidirectional transport of lipids between these lipoproteins and cells 1 . In the liver, SR-BI is involved in the uptake of cholesterol from HDL and its excretion in bile, the final step in reverse cholesterol transport. SR-BI also participates in the uptake of cholesterol in steroidogenic tissues, such as the adrenal glands and ovaries, to be used as a substrate for steroid hormone synthesis 2 . Important information on the roles of SR-BI other than in cholesterol homeostasis and cholesterol provision for steroidogenesis, such as platelet aggregation, erythrocyte maturation and oocyte meiosis, has been generated from the SR-BI knock out (SR-BI −/− ) mouse since it was generated almost two decades ago 3 .In generating SR-BI −/− mice via heterozygous intercrosses, researchers noted that the proportion of weaned homozygous null mice was half that expected by the Mendelian ratio 3 . This evidence, together with the fact that SR-BI is present in murine trophoblasts involved in maternal-foetal nutrient exchange at different stages of gestation 4 , led researchers to postulate that this HDL receptor might be involved in embryonic development. We recently showed that nearly 50% of SR-BI −/− embryos fail to close the anterior neural tube and develop cranial NTD and exencephaly 5 , leading to perinatal death, which explains the deviation from the Mendelian ratio previously reported in weaned SR-BI null mice 3 . Among the spectrum of defective neurulation conditions conferred by abnormal closure at different portions of the neural tube, only cranial NTD is observed in SR-BI −/− embryos.During murine early development, SR-BI is not detected in the embryo itself but rather in trophoblast giant cells (TGC) from the parietal yolk sac 4,5 . TGC play a critical role in embryonic uptake of various nutrients from the maternal blood supply before the establishment of a mature placenta 6 . Despite the prominent role of SR-BI

High density lipoproteins (HDL) take up cholesterol from peripheral tissues via ABC transporters and deliver it to the liver via scavenger receptor class B type I (SR-B1). HDL are the main lipoproteins present in follicular fluid (FF). They are thought to derive from plasma, but their origin is still controversial. SR-B1 knock-out (KO) mice have provided important evidence linking HDL metabolism and female fertility. These mice have cholesterol-rich circulating HDL and female infertility that can be restored by treating mice with the cholesterol-lowering drug probucol. Ovulated oocytes from SR-B1 KO females are dysfunctional and show excess cholesterol. The mechanisms explaining the contribution of FF HDL to oocyte cholesterol homeostasis are unknown. Here, using quantitation of filipin fluorescence we show that in SR-B1 KO ovaries, cholesterol excess is first observed in immature oocytes in antral follicles. By performing cross-transplant experiments between WT and apolipoprotein A-I deficient (ApoA-I KO) mice, which lack the main protein component of HDL, we provide evidence supporting the plasmatic origin of FF HDL. Also, we demonstrate that probucol treatment in SR-B1 KO females results in lowering of cholesterol content in their oocytes. Incubation of oocytes from SR-B1 KO mice with purified WT HDL reduces their cholesterol content, suggesting that HDL promote efflux of excess cholesterol from oocytes. In agreement with this hypothesis, we identified ABC transporters in oocytes and observed that ABCA1 KO oocytes have excess cholesterol and lower viability than WT oocytes.

Summary The absorption and elimination of cefquinome in serum and tissues of coho salmon were studied. The study was performed in freshwater at 10°C with fish weighing 100 ± 5g (mean and standard deviation). Single doses of 5, 10 and 20 mg/kg were administered intraperitoneally to 30 fish for each dose. The maximum concentration occurred in the following order; kidney and liver > serum > muscle > brain. The pharmacokinetic analysis and predictive withdrawal times were calculated using only the dose of 20 mg/kg body weight. The peak cefquinome concentrations (Cmax) in serum (3.35 ± 0.45 μg/ml) and muscle (2.87 ± 0.53 μg/g) were achieved at 12h. In the brain, the Cmax was 2.18 μg/g at 6h. The halflives (t1/2) in serum, muscle, brain, liver and kidney were 20.56, 8.93, 9.35, 113.61 and 119.48 h, respectively. With the detection limit of 0.015 μg/g for the cefquinome, the predicted withdrawal time with 95% confidence for muscle tissue was 104.2 h at 10 °C for the 20 mg/kg dose. The results suggest that cefquinome could be efficacious and safe for the consumer in treating bacterial diseases of coho salmon in fresh water. Nevertheless, future studies are required in order to determine an adequate dose with the corresponding withdrawal times.

Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels of this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes its synthesis and uptake from circulating lipoproteins. In contrast, its excess induces the efflux to high-density lipoproteins (HDL) and their transport to the liver for excretion, a process known as reverse cholesterol transport. Different studies suggest that an abnormal HDL metabolism hinders female fertility. HDL are the only lipoproteins detected in substantial amounts in follicular fluid (FF), and their size and composition correlate with embryo quality. Oocytes obtain cholesterol from cumulus cells via gap junctions because they cannot synthesize cholesterol de novo and lack HDL receptors. Recent evidence has supported the possibility that FF HDL play a major role in taking up excess unesterified cholesterol (UC) from the oocyte. Indeed, genetically modified mouse models with disruptions in reverse cholesterol transport, some of which show excessive circulating UC levels, exhibit female infertility. Cholesterol accumulation can affect the egg´s viability, as reported in other cell types, and activate the plasma membrane structure and activity of membrane proteins. Indeed, in mice deficient for the HDL receptor Scavenger Class B Type I (SR-B1), excess circulating HDL cholesterol and UC accumulation in oocytes impairs meiosis arrest and hinders the developmental capacity of the egg. In other cells, the addition of cholesterol activates calcium channels and dysregulates cell death/survival signaling pathways, suggesting that these mechanisms may link altered HDL cholesterol metabolism and infertility. Although cholesterol, and lipids in general, are usually not evaluated in infertile patients, one study reported high circulating UC levels in women showing longer time to pregnancy as an outcome of fertility. Based on the evidence described above, we propose the existence of a well-regulated and largely unexplored system of cholesterol homeostasis controlling traffic between FF HDL and oocytes, with significant implications for female fertility.

BackgroundThe high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD.ResultsWe used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism.ConclusionsOur analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5110-2) contains supplementary material, which is available to authorized users.