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BOR - Papers in Press, published online ahead of print March 31, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.028092
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BIOLOGY OF REPRODUCTION 71, 479–485 (2004)
DOI: 10.1095/biolreprod.104.028092
© 2004 by the Society for the Study of Reproduction, Inc.

Ovary

Lipid Transport in the Developing Bovine Follicle: Messenger RNA Expression Increases for Selective Uptake Receptors and Decreases for Endocytosis Receptors

Nurit Argov2, Uzi Moallem3, and David Sklan1,2

Faculty of Agriculture,2 Hebrew University, Rehovot, 76-100, Israel Department of Dairy Cattle,3 Institute of Animal Sciences, Volcani Center, Bet-Dagan, 50250 Israel


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Differences in rates of steroid production and secretion will, eventually, determine the developmental rates of ovarian follicles. The major supply of cholesterol, the precursor for steroid and androgen biosynthesis, to ovarian cells is from circulating lipoproteins via membrane receptors from the low density lipoprotein receptor (LDL) superfamily. This occurs by either endocytosis, which has been described for very low density lipoprotein receptors (VLDLr), for LDL receptors (LDLr), and by the selective uptake pathway described for the scavenger receptor class B type 1 receptor (SRB1) and the recently described ovarian receptor, lipoprotein receptor-related protein 8 (LRP8). In this study, the mRNA expression of these four cholesterol receptors in bovine ovarian cells was determined at different stages of follicular development. In small antral follicles, mRNA expression of the endocytosis receptors was higher than in large antral follicles. Expression of LRP8 mRNA increased linearly with follicular size together with an increase in LDL, VLDL, and cholesterol concentrations in the follicular fluid. SRB1 mRNA expression tended to increase with follicular diameter. Because different mRNA expression patterns were found for the two types of receptor, this may imply different regulation of cholesterol supply at different stages of follicular development. Accumulation of LDL and VLDL particles in the follicular fluid of large antral follicles may enhance cholesterol availability for the intense steroidogenic activity that is essential at these stages.

follicle, follicular development, steroid hormones


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cholesterol is the precursor of steroid hormones in all steroidogenic tissues [1], and steroid hormones are instrumental in ovarian follicular development. Differences between steroidogenic ability of the different follicles control which will undergo selection, which is determined by the highest estradiol-to-progesterone ratio in follicular fluid [2]. Cholesterol obtained from plasma is transported to the inner mitochondrial membrane in ovarian cells where it is cleaved initially by the cytochrome P450 side chain cleavage enzyme complex. Hence, the ability to produce steroid hormones depends on cholesterol availability to the mitochondrial enzymes.

Lipoprotein particles secreted from the intestine or liver contain specific apolipoproteins, which are involved in the targeted delivery of lipoproteins to cells via receptor-mediated pathways [3]. These lipid particles contain cholesterol in different ratios in accordance with the lipoprotein class. A secondary source of cellular cholesterol is from de novo synthesis.

The connection between circulating lipoproteins, their cholesterol component, and estradiol was first postulated due to the sharp increase in cardiovascular diseases in postmenopausal women, when circulating estradiol levels decrease [4]. In addition, in the mouse, expression of the steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, was found to be regulated by lipoprotein at the transcriptional level [5]. Thus, regulation of the StAR gene expression by low density lipoprotein (LDL) may represent a positive feedback that links cholesterol availability and steroid output. Cholesterol homeostasis in mammalian cells is regulated by a unique family of transcription factors called sterol regulatory element binding proteins (SREBP) [6]. Sterol regulatory elements have been identified in the 5'-flanking regions of sterol-regulated genes, such as LDLr and StAR, [7]. Steroidogenic cells obtain cholesterol from the circulation by two pathways. The first pathway involves endocytosis, which was described for the low density lipoprotein receptor (LDLr) and the very low density lipoprotein receptor (VLDLr) [8, 9]. In the LDLr gene, the sterol regulatory element 1 (SRE1) contains the information necessary for mediation of sterol regulation [10], and this regulation is through SREBP 1a and 2, which regulate transcription [11]. Another regulatory element for these genes is estrogen, which activates estrogen-response elements and may cause enhancement or repression of transcription of estrogen-sensitive genes [4].

An additional cholesterol uptake pathway was described after monitoring the endocytotic rate of chylomicron remnants by hepatic cells of LDLr knockout mice [12]. In this pathway, circulating lipoproteins contribute their cholesterol esters without internalization of the lipoprotein particle, which has thus been termed selective uptake. The high-density lipoprotein (HDL) receptor-scavenger receptor class B type 1 (SRB1) has been shown to mediate this selective uptake of cholesterol esters in liver and steroidogenic tissues [13]. SRB1 was also shown to be critical in reproductive physiology, as has been demonstrated with knockout mice [14]. Gene expression of SRB1 was found in theca cells of the immature mouse ovary. In the first stages of folliculogenesis, mRNA for SRB1 was only detected in the theca cells [15]. The SRB1 mRNA expression was upregulated after hCG, insulin, and LH treatment [11] and was connected to FSH in human granulosa cells [16], which indicates a close connection between hormones causing follicular development and genes connected to cholesterol supply to the steroidogenic ovarian cells. Another study in the rat ovary [17] used in situ hybridization to show that SRB1 mRNA was expressed in all ovarian cells. Different tissue regulation of estradiol on SRB1 mRNA expression was observed after estrogen treatment, which decreased SRB1 mRNA in hepatic tissues but enhanced its expression in peripheral tissues such as the ovary [13].

Another receptor that takes part in cholesterol ester-selective uptake is the lipoprotein receptor-related protein 8 (LRP8) [18]. LRP8 is a multifunction receptor that binds a diverse spectrum of ligands, including lipoproteins, proteases, and their inhibitors, peptide hormones, and carrier proteins for vitamins [19]. LRP8 has more than one binding domain [20], and it has been postulated that binding to some domains will activate cholesterol uptake and to others will activate intracellular signaling. The role of LRP in lipoprotein remnant catabolism and protease regulation has been described [15, 21]. Recently, we have described the presence of LRP8 mRNA in bovine ovarian cells, but its role has not been elucidated [22].

The lipid supply to the ovary has only been partially described. The LDLr and VLDLr were found in human ovarian cells only in preovulatory follicles [23] or in luteinized granulosa cells [24]. In rat theca cells, involvement of genes of the LDLr superfamily was shown [25]. In porcine granulosa and theca cells, mRNA for LDLr was not found in early follicular developmental stages [26] and VLDLr mRNA was found only in bovine preovulatory follicles [23]. Thus, characterization and quantification of the mechanisms enabling developing follicular cells to obtain cholesterol for steroid biosynthesis and follicular development have not been detailed. This study describes the quantitative expression of different genes involved in cholesterol internalization and determines lipid concentrations in the developing bovine follicle; these data provide insight into regulation of steroid hormone production.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Ovarian Cells

Bovine ovaries were collected fresh from a slaughterhouse, washed with sterile serum, and transferred at 37°C to the laboratory. Follicles were dissected under sterile conditions from the ovary and washed with sterile saline from any remaining adhering tissue. Healthy developing follicles were assessed by the following criteria: vascularized pink theca externa and clear amber follicular fluid with no debris [27]. The diameter of healthy follicles was determined and follicles were divided into four groups by diameter: 1) small antral follicles, 2–4 mm; 2) medium-sized antral follicles, 4–8 mm; 3) large- to medium-sized antral follicles, 8–10 mm; and 4) large-sized antral follicles, >10 mm. Follicular fluid was aspirated, and the follicles were snap frozen in liquid nitrogen. At least six follicles from different ovaries were examined at each diameter.

Total RNA Isolation

Total RNA was isolated using TRI reagent (10 ml/g tissue) according to the manufacturer's protocol (MRC Molecular Research Center, Cincinnati, OH).

The mRNA Analysis

First-strand cDNAs were synthesized from 5 µg of total RNA of each follicle using oligo(dT)18 as primers in the presence of MLV reverse transcriptase (Fermentas Inc., Hanover, MD) for 1 h at 42°C. The cDNA was purified from the polymerase chain reaction (PCR) mix using High Pure PCR Product Purification kit (Roche Diagnostics GmbH, Mannheim, Germany). PCR was carried out with primers for LDLr, VLDLr, LRP8, and GAPDH (Table 1). SRB1 primers were as described by Rajapaksha et al. [28]. Determination of the logarithmic phase of the amplification was performed with Pfu DNA polymerase (Promega Corporation, Madison, WI) with pooled cDNA aliquots removed at 10, 15, 20, 25, 30, 35, 40, and 45 cycles. In subsequent reactions, amplification of the ovarian LDLr and VLDLr genes was performed for 42 cycles; for LRP8, 32 cycles; and for SRB1, 37 cycles, which consisted of denaturation (95°C, 30 sec), annealing (59°C, 1 min), and extension (72°C, 2 min), and GAPDH was amplified at 30 cycles under the same conditions in a different tube. PCR products were separated by electrophoresis on 1.5% agarose gel, stained with ethidium bromide, and quantified using Gel-Pro Analyzer, version 3.0 (Media Cybernetics, LP, Silver Spring, MD). The mRNA from each follicle was examined in duplicate for all receptors.


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  		TABLE 1. Primer sequences and concentrations

Lipoprotein Analysis

Lipoproteins in plasma and follicular fluid were determined by gel filtration as previously described [29] using a TSK 4000 column (Pharmacia Inc., Uppsala, Sweden) calibrated with standards of known Mr. Separation of the lipoprotein components from follicular fluid from large antral follicles was confirmed by ultracentrifugation for 24 h at 104 000 x g in sucrose solutions of specific gravity of 1.006, 1.07, and 1.25. Top and bottom fractions were taken for cholesterol and fatty acid (FA) determination.

Fatty Acid Analysis

Fatty acids were determined by gas chromatography using an internal standard of heptadecanoic acid as previously described [30].

Total Cholesterol

Total cholesterol content was determined after saponification using a modified Lieberman-Buchard reaction as previously described [31].

Statistical Analyses

Data were analyzed by analysis of variance and linear regression using the general linear models procedures of SAS [32]. Differences between means were tested using Tukey test and significance was P < 0.05 unless otherwise stated.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Follicular Fluid Lipoprotein Concentrations

Lipoproteins were separated by gel filtration and concentrations are presented as determined from absorption at 280 nm. HDL-type particles were the major lipoprotein in all samples. Proportions of LDL and VLDL were higher in large antral follicles (sizes 3 and 4) than in plasma. In contrast, in small antral follicles (sizes 1 and 2), lipoprotein proportions were not different from plasma (Fig. 1). It should be noted that the protein content of lipoproteins is VLDL 9%, LDL 21%, and HDL 50%.



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  		FIG. 1. Relative composition of lipoproteins in follicular fluid of large (size 4) and small (size 1) antral follicles as a percentage of total lipoproteins determined after gel filtration by absorption at 280 nm. Bars are means ± SD (n = 6) and bars not followed by the same letter differ (P < 0.05). In large antral follicles, proportions of VLDL + LDL and HDL were different from plasma, with higher proportions of VLDL and LDL and lower HDL, whereas in small antral follicles, proportions in follicular fluid and plasma were not different

Follicular Fluid Cholesterol and Fatty Acid Concentrations

Total cholesterol concentration in follicular fluid was higher in large antral follicles (size 4) than in small antral follicles (sizes 1 and 2). Follicles of intermediate size (size 3) had cholesterol concentrations that were not different from large antral follicles (Fig. 2). Cholesterol concentrations were positively correlated with follicular size (cholesterol = 18.85 + 3.99 x size, r = 0.82, P < 0.0001). Total FA content in small antral follicles were higher than all other follicular sizes (2, 3, and 4) (Fig. 3), and fatty acid concentrations were negatively correlated with follicular size (FA = 1510.4 – 84.8 x size, r = 0.60, P < 0.008). Changes in the FA profile with follicular size were observed. In small antral follicles, saturated fatty acids were present in higher and polyunsaturated fatty acids in lower proportions then in large antral follicles (Table 2).



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  		FIG. 2. Cholesterol concentrations (µg/ml) in follicular fluid from follicles of different sizes. Bars represent means ± SD (n = 8), bars not followed by the same letter differ (P < 0.05). Cholesterol concentrations in small antral follicles (size 1) were lower than in all other follicular sizes. In large antral follicles (size 4), cholesterol concentrations were higher than in size 2 follicles but were not different from follicles of size 3



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  		FIG. 3. Total FA (µg/µl) in follicular fluid obtained from follicles of different sizes. Bars are means ± SD (n = 6) and bars not followed by the same letter differ (P < 0.05). In small antral follicles (size 1), total FA concentration was highest and differed from all the other follicular sizes


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  		TABLE 2. Fatty acid (FA) composition of follicular fluid from follicles at different developmental stages (percentage of total FA).*

The mRNA Expression

Expression of mRNA for receptor genes connected with lipid transport was determined in follicles at different stages of development. Expression of mRNA for LDLr was high in small antral follicles (sizes 1 and 2) and decreased linearly with increasing follicular size (LDLr = 5.32 – 0.39 x size, r = 0.61, F = 0.007). The expression of mRNA for LDLr decreased between small and large antral follicles by more than 20-fold (Fig. 4). VLDLr mRNA expression was also highest in small antral follicles (size 1) and decreased linearly with follicle size (VLDLr = 28.45 – 2.08 x size, r = 0.7, F = 0.0012). Levels of expression decreased by approximately 10-fold between small and large antral follicles, but expression was still considerable in large follicles (Fig. 4). The pattern of SRB1 mRNA expression was different from that of the LDLr and VLDLr, with expression of mRNA lowest in small antral follicles (size 1), and tended to increase in large antral follicles (sizes 3 and 4). No linear correlation was found between SRB1 mRNA expression and follicular size (Fig. 4). Expression of LRP8 mRNA was found in follicles of all sizes and increased linearly with follicular diameter (LRP8 = 0.78 + 0.18 x size, r = 0.44, F = 0.07), where the increase in expression between small and large antral follicles was approximately 2-fold.



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  		FIG. 4. Expression of mRNA of the genes encoding for mRNA of LDLr, VLDLr, SRB1, and LRP8 was determined by semi-quantitative polymerase chain reaction. Bars are means ± SD (n = 6) and bars not followed by the same letter differ (P < 0.05). LRP8 mRNA (top left) increased linearly with follicular diameter. SRB1 mRNA expression (top right) tended to increase with follicular size, as its expression was lowest in small antral follicles (size 1) and significantly elevated in large antral follicles (sizes 3 and 4). Expression of mRNA for LDLr (bottom left) was high in small antral follicles (sizes 1 and 2) and decreased linearly with follicular size. VLDLr mRNA expression (bottom right) was also highest in small antral follicles (size 1) and decreased linearly with follicle size

Interactions

Expression of mRNA for LDLr and VLDLr were correlated (LDLr = 0.78 + 0.13 x VLDLr, r = 0.62, P < 0.007). Expression of LDLr mRNA was negatively correlated with cholesterol concentrations in follicular fluid (LDLr = 5.45 – 0.06 x cholesterol, r = 0.47, P < 0.05), and expression of VLDLr mRNA was also negatively correlated with cholesterol concentrations in follicular fluid (VLDLr = 34.04 – 0.43 x cholesterol, r = 0.69, P < 0.001). Cholesterol and total fatty acid concentrations in follicular fluid were negatively correlated (cholesterol = 68.1 – 0.022 x FA, r = 0.64, P < 0.004).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study describes the expression of receptors involved in lipid transport in developing bovine ovarian follicular cells and suggests involvement of LRP8 in selective uptake processes that play a major role in cholesterol supply to large antral follicles.

Regulation of lipoprotein endocytosis has been extensively described in different cell types, whereas in the ovary this has been studied mainly in preovulatory follicles [23]. Sterol-regulated genes are transcribed actively when animal cells require cholesterol and are repressed when sterol accumulates [10]. Sterol-mediated repression of transcription has been demonstrated for the gene encoding LDLr [7], the promoter of which contains a sterol regulatory element [33]. In the present study, in large antral follicles, where steroid hormones are being produced in high amounts, LDLr mRNA expression was lower than in small follicles, possibly due to the higher sterol content. LDL and VLDL concentrations increased in the follicular fluid of large antral follicles, possibly because their uptake decreased due to downregulation of LDLr mRNA expression. However, this may also be due to permeability changes of the basal membrane with follicular development [34]. In contrast, in small antral follicles, where cholesterol concentration was lower and the lipoprotein content was not different from the plasma, significantly higher mRNA expression of LDLr was found. In both porcine and caprine developing follicles, FA concentration decreased with follicular size [35, 36]. The fact that the follicular fluid from small antral follicles contained low cholesterol concentrations and higher FA levels is explained by the relatively higher amounts of HDL in these follicles because HDL contains relatively less cholesterol and higher FA [37]. In small antral follicles, the low concentrations of LDL and VLDL maintain the LDLr and VLDLr mRNA at high levels.

Accumulation of LDL in the follicular fluid might also be explained via an effect on insulin. Addition of LDL enhanced insulin action on porcine granulosa cells [38]. Insulin has many effects on granulosa cells, such as enhancing proliferation and increasing biosynthesis of ovarian hormones through specific enhancement of steroidogenic enzymes. The enrichment of the LDL fraction in follicular fluid in large follicles may increase follicular sensitivity to insulin and increasing estradiol production and secretion.

The VLDLr is another endocytotic membrane receptor from the LDLr superfamily [39]. The mRNA for the two endocytotic receptors changed in parallel throughout follicular development, with mRNA expression for both genes high in small antral follicles and decreasing with follicular growth. The VLDLr does not appear to be regulated in parallel with LDLr, as mRNA expression of VLDLr was not affected in rabbit macrophages with increasing concentrations of cholesterol in the culture medium [40]. It is possible, in the present study, that mRNA of VLDLr was not decreased due to the elevated cholesterol concentration in the follicular fluid, but due to the increased production and secretion of estradiol by granulosa cells to the follicular fluid which occurs in large antral follicles [41].

In the present study, in parallel with the elevated cholesterol concentration in the follicular fluid of large antral follicles, decreased FA concentration was found. This may result from the different lipoprotein contents in the follicular fluid of follicles in the diverse developmental stages. As was found in the present study, the proportions of LDL and VLDL levels were lowest in small antral follicles; however, HDL lipoprotein levels were higher in these follicles. LDL has the highest cholesterol:FA ratio, whereas HDL has the lowest ratio [37]. This may explain the high amounts of cholesterol and low amounts of FA found in large antral follicular fluid as opposed to the concentrations in small antral follicles. The different FA composition that was found in follicular fluid of different developmental stages may indicate selective use of polyunsaturated FAs, which participate in both energy supply and as part of the structure of membrane phospholipids [42]. In advanced follicular developmental stages, the polyunsaturated FA levels in the follicular fluid were elevated, as previously reported in porcine [36], and a corresponding decrease of the saturated FA content was found, indicating that the follicular cells preferentially use FA for energy purposes as granulosa cells are proliferating at very high rates [43]. These findings are supported by a report showing that peroxisome proliferator-activated receptors are influenced by intracellular nonesterified fatty acids [44].

An additional pathway for cholesterol uptake has been described where selective uptake of cholesterol esters rather than internalization of intact lipoprotein particles occurs. This was described for SRB1 in follicular cells [45]. In the present study, SRB1 mRNA increased with the follicular developmental phase. The major lipoprotein particle in plasma and follicular fluid of the bovine is HDL, and SRB1 utilizes the cholesterol from this source for selective transport. The fact that, in large antral follicles, the LDLr and VLDLr mRNA decreased dramatically also contributes to accumulation of LDL and VLDL lipid components in the follicular fluid. Although cholesterol depletion in ovarian follicular fluid was shown to increase mRNA expression of SRB1 [11], SRB1 mRNA in the present study tended to increase with follicular size and higher cholesterol levels in the follicular fluid. In rat ovarian cells, SRB1 protein distribution increased after high doses of estradiol [13]. These results are in accordance with those in the present study, which showed that SRB1 mRNA increased in large antral follicles. In these stages of development, estradiol production and secretion are elevated [41]; thus, the follicular cells are exposed to high concentrations of estradiol, which apparently causes increased SRB1 mRNA expression. The fact that SRB1 was found to be induced by insulin [11] may also explain the tendency for increased SRB1 mRNA expression in large antral follicles because insulin content of follicular fluid also increased with follicular growth [46].

An additional member of the lipoprotein receptor family, LRP8, also participates in selective uptake of cholesterol in different tissues [21] and in ovarian cells [22]. In human blood mononuclear cells, dietary cholesterol increased LRP mRNA levels [47] and, in macrophages, LRP8 was upregulated in cells incubated with cholesterol [48]. These results are similar to the mRNA expression pattern found in the present study that showed a positive correlation with follicular size and cholesterol concentration. Expression of mRNA for LRP8 increased with follicular development whereas mRNA for LDLr and VLDLr decreased with increasing follicular diameter. Thus, the increase in LRP8 mRNA expression in follicular cells may imply that this receptor participates in the mechanisms supplying cholesterol, allowing some control of cholesterol internalization in accordance with the developmental phase of the follicle.

The two selective uptake receptors examined here, SRB1 and LRP8, use different lipoprotein particles to obtain cholesterol. Although a major lipid component of the HDL particle is phospholipids, the SRB1 utilizes this particle to obtain cholesterol esters [13]. In cattle, the major plasma lipoprotein is HDL [49], which may explain the levels of mRNA of this receptor in the developing follicle. In contrast, LRP8 has different ligands and may obtain cholesterol esters from lipoprotein particles containing apoE or apoB, which is the major apoprotein of LDL [37]. Hence, with changes in the mRNA expression of SRB1 and LRP8 in the follicular cells of large antral follicles, LDL concentration in the follicular fluid increases because LDL particles are not internalized although cholesterol may be extracted by LRP8. The only receptor of which mRNA expression increases with follicular size and follicular cholesterol demands is LRP8, which suggests that this receptor may have a role in cholesterol supply for steroid biosynthesis, which enables folliculogenesis and selection processes to occur. The negative feedback between steroidogenic status and mRNA expression of genes connected to sterol uptake by the endocytosis pathway reduces cholesterol supply by this route in large follicles, whereas such regulation is not found for genes for selective uptake receptors.


   FOOTNOTES
 
1 Correspondence: D. Sklan, Faculty of Agriculture, PO Box 12, Rehovot, 76-100, Israel. FAX: 972 8 9489865; Sklan{at}agri.huji.ac.il Back

Received: 2 February 2004.

First decision: 24 February 2004.

Accepted: 25 March 2004.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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