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Endocrinology Vol. 139, No. 1 72-80
Copyright © 1998 by The Endocrine Society

ARTICLES

Characterization and Chromosomal Localization of Rat Scavenger Receptor Class B Type I, a High Density Lipoprotein Receptor with a Putative Leucine Zipper Domain and Peroxisomal Targeting Sequence1

Magnus S. C. Johnson, Per-Arne Svensson, Khalil Helou, Håkan Billig, Göran Levan, Lena M. S. Carlsson and Björn Carlsson

Research Center for Endocrinology and Metabolism (M.S.C.J., P.-A.S., L.M.S.C., B.C.), Department of Internal Medicine, and Center for Reproductive Medicine (H.B.), Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, and the Departments of Genetics (K.H., G.L.), Göteborg University, S-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Dr. Björn Carlsson, Research Center for Endocrinology and Metabolism, Department of Internal Medicine, Gröna Stråket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: bjorn.carlsson{at}ss.gu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
High density lipoprotein (HDL) participates in reverse cholesterol transport and in the delivery of cholesterol to steroid-producing tissues. Scavenger receptor class B type I (SR-BI) was recently shown to bind HDL and mediate internalization of its cholesterol content. We have cloned the rat homolog of this receptor, determined its chromosomal location, and examined its expression in rat tissues and in a model of follicular development, ovulation, and luteinization. The predicted protein contained two transmembrane domains, a leucine zipper motif, and a peroxisomal targeting sequence. The rat and human SR-BI genes were mapped to a region previously linked between rat and human chromosomes 12. SR-BI gene expression was detected in several rat tissues, with high levels in ovarian tissue, liver, and adrenal cortex, as determined by ribonuclease protection assay and in situ hybridization. A significant increase in SR-BI gene expression was detected in the late phase of corpus luteum formation, and transcripts were abundant in corpus luteum and in thecal cells at all stages of follicular development. In conclusion, the rat SR-BI complementary DNA predicted a protein with several conserved motifs, including a putative leucine zipper and a peroxisomal targeting sequence. The chromosomal locations of the rat and human SR-BI homologs suggest that this gene is a new member of a previously reported, conserved synteny group. SR-BI gene expression was high in steroid-producing tissues and in the liver, consistent with a role of this receptor in the uptake of HDL cholesterol.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LOW SERUM levels of high density lipoprotein (HDL) along with high serum levels of low density lipoprotein (LDL) are well recognized risk factors for cardiovascular disease (1, 2, 3, 4, 5). The uptake and degradation of LDL cholesterol have been characterized in detail at the molecular level and involve receptor-mediated endocytosis (6). Less is known about the metabolism and cellular uptake of HDL cholesterol. HDL cholesterol delivery appears to involve receptor-mediated binding of HDL followed by selective uptake of cholesteryl esters without internalization of the protein component, mainly apolipoproteins A-I and A-II (apo A-I and apo A-II) (7, 8, 9, 10, 11, 12, 13). Acton and co-workers recently showed that scavenger receptor class B type I (SR-BI) binds HDL and mediates uptake of HDL cholesteryl esters (14). SR-BI is expressed at all major sites of selective cholesterol uptake, including adrenal gland, ovary, testis, and liver (9, 15, 16). The importance of apo A-I-mediated HDL cholesterol delivery to steroidogenic tissues was recently demonstrated by Plump and co-workers (17). Disruption of the apo A-I gene in mice caused severe deficiency of cholesterol esters in the ovary and adrenal gland and decreased the production of corticosteroids (17). The uptake of HDL cholesterol ester in the liver is believed to be of importance for reverse cholesterol transport. Nonhepatic peripheral tissues obtain their cholesterol from a combination of local synthesis and uptake of preformed sterol from plasma lipoproteins. Reverse cholesterol transport is the opposing movement of cholesterol from peripheral tissues via the blood to the liver, where it joins the intracellular feedback-regulated cholesterol metabolism and is excreted or recirculated (18, 19). Adenovirus-mediated overexpression of the HDL receptor SR-BI in the liver leads to reduced plasma HDL levels and increased cholesterol secretion into bile (20).

The aim of this study was to characterize the cloned rat homolog of SR-BI (GenBank accession no. U76205), to determine the chromosomal localization, and to study its regulation and cellular distribution in the rat ovary.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The use of animals in this study was approved by the local ethics committee for animal care and use (Göteborg, Sweden). Female Sprague-Dawley rats (Alab, Stockholm, Sweden) were housed under standardized environmental conditions with constant temperature (24–26 C), humidity (50–60%), and an artificial 14-h light and 10-h dark cycle. The animals had free access to water and pelleted food. To induce follicular development, immature rats were injected sc on day 25 with 10 IU PMSG (Sigma Chemical Co., St. Louis, MO) and killed 2 days later (21). Untreated immature rats of the same age served as controls. To study early and late luteal phases of corpus luteum formation, immature rats were given 10 IU PMSG followed by 25 IU hCG (Leo, Helsingborg, Sweden) 2 days later and killed 12 and 48 h after hCG administration, respectively (22). Rats were killed by cervical dislocation, and tissues were immediately removed and trimmed with microscissors. Granulosa cells were isolated from PMSG-stimulated ovaries by incising the largest follicles under a stereomicroscope. The remaining tissue, consisting of small follicles and thecal and interstitial cells, was isolated and designated residual ovary. After isolation, tissue and cells were rapidly frozen in liquid nitrogen and stored at -70 C until analyzed.

Cloning and complementary DNA (cDNA) sequencing
RNA was extracted according to Chomczynski and Sacchi (23). First strand cDNA was obtained by reverse transcription of rat liver RNA using AMV reverse transcriptase (Promega, Madison, WI). To obtain the nucleotide sequence of the coding region of the rat SR-BI cDNA, two overlapping cDNA fragments were amplified by PCR using two sets of degenerate primers, designed based on highly conserved regions of the Chinese hamster and mouse SR-BI cDNAs (14, 24) (GenBank accession no. U11453 and U37799, respectively). PCR using the first primer pair (c5, 5'-GTCTCCTTCAGKYCCTGA-3'; c3, 5'-TGAGGATTCGGGTGTCAT-3') resulted in an 861-bp fragment corresponding to nucleotides -48 through 813 of rat SR-BI cDNA. The second primer pair (p5, 5'-ACTTCCGGGCAGATGTGG-3'; b3, 5'-TCCGCTGAGAGAGTCCTCAA-GAAGCGG-3') resulted in an 858-bp fragment corresponding to nucleotides 769 through 1626. PCRs were performed in Taq Extender buffer (Stratagene, La Jolla, CA) using 1 µl of a 1:1 (vol:vol) mixture of Taq (5 U/µl; Boehringer Mannheim, Mannheim, Germany) and Pfu (2.5 U/µl; Stratagene) in a total volume of 50 µl. A PCR GenAmp System 9600 (Perkin-Elmer, Foster City, CA) was programed for "hot start" at 94 C (4 min) followed by a step-down procedure with a total of 25 cycles, and annealing temperatures decreased by 1 degree every third cycle from 52 to 48 C and extension at 72 C for 1 min. Fragments were subcloned into the pCRII vector (Invitrogen/British Biotechnology, Oxon, UK). For each of the two cDNA fragments, three subclones, derived from three separate PCR reactions, were sequenced using reverse (-21) and forward M13 dye primers according to the Applied Biosystems PRISM dye primer cycle sequencing ready reaction kit (Perkin-Elmer) and an Applied Biosystems 377 automatic sequencer (Perkin-Elmer). Sequence Editor (Applied Biosystems, Foster City, CA), MacVector (Eastman Kodak, Rochester, NY), DNA star (Lasergene, Madison, WI) sequence analysis software, and the Entrez Blast Program (NCBI, Bethesda, MD; URL: http://www.ncbi.nlm.nih.gov/cgi-bin/BLAST) were used for analysis of nucleotide and amino acid sequences.

Probes
RT-PCR of total RNA from rat liver was used to obtain probes for the RPA, in situ hybridization, and fluorescent in situ hybridization (FISH). A 393-bp cDNA fragment spanning nucleotides 769-1161 was obtained by RT-PCR from liver cDNA, using primers pair p5 (see above) and p3 (5'-CTTCACAGAACAGTTCAT-inosine-GG-3') and subcloned into pBSKII (Stratagene), generating plasmid pMJ5:101. A 1494-bp fragment spanning nucleotides -48 through 1446, using primer pair c5 (see above) and q3 (5'-CTGCGAGCCCTTTTT-ACT-3') was subcloned into pCRII (Invitrogen), generating plasmid pMJ4:126–18.

RNA probe synthesis
[{alpha}-33P]UTP-labeled antisense rat SR-BI RNA was generated by in vitro transcription with T3 polymerase using HindIII-linearized plasmid pMJ5:101. [{alpha}-33P]UTP-labeled sense rat SR-BI RNA was generated by in vitro transcription with T7 polymerase using SpeI-linearized pMJ5:101 as template. Antisense rat ß-actin [{alpha}-33P]UTP-labeled RNA was generated by in vitro transcription with T7 polymerase using the EcoRI-linearized plasmid pBSKII-ß-actin as template.

Ribonuclease (RNase) protection assay
Fifty micrograms of RNA from rat tissues were hybridized with 200,000 cpm [{alpha}-33P]SR-BI probe and 200,000 cpm [{alpha}-33P]ß-actin probe and RNase digested as described in the RPA II kit manual (Ambion, Austin, TX). The protected fragments were separated on a 6% acrylamide gel and visualized using a Molecular Dynamics PhosphorImager System (Sunnyvale, CA). Densitometry was performed with the ImageQuant software (Molecular Dynamics).

In situ hybridization
Ovaries were removed, frozen on dry ice, and stored at -70 C. Ovarian sections (10 µm) were cut at -20 C, thaw-mounted onto Superfrost Plus slides (Erie Scientific, Portsmouth, NH), and stored at -70 C. Frozen sections were thawed (at room temperature for 5 min), fixed in 4% paraformaldehyde, acetylated, dehydrated through graded ethanol solutions, and delipidated in chloroform before hybridization, as previously described (21). 33P-Labeled SR-BI antisense and sense RNA (1 x 106 cpm), generated from pMJ5:101, were hybridized to two adjacent sections on each slide. Sections were hybridized overnight at 50 C in a humid chamber in buffer containing denatured probe in 50% formamide, 0.025 M Tris (pH 7.5), 0.001 M EDTA (pH 8.0), 0.4 M NaCl, 1 x Denhardt’s solution (0.02% Ficoll, 0.02% polyvinylpyrrolidone, and 0.02% BSA), 10% dextran sulfate (mol wt, 500,000), single stranded testis DNA (250 µg/ml), and yeast transfer RNA (250 µg/ml). Sections were washed in 2 x SSC (standard saline citrate; at room temperature) and twice in 2 x SSC-50% formamide (at 50 C for 15 min), rinsed briefly in 2 x SSC (at 37 C), incubated in 2 x SSC containing RNase A (100 µg/ml; at 37 C for 30 min), rinsed in 2 x SSC, washed three times in 2 x SSC-50% formamide (at 50 C for 15 min each) and twice in 2 x SSC (at room temperature for 5 min), dipped in water, dehydrated through graded ethanol, and air-dried. Slides were exposed for 24 h and visualized using a PhosphorImager System (Molecular Dynamics; Fig. 3bGo) and to autoradiographic emulsion (LM-1, Amersham International, Amersham, Aylesbury, UK) for up to 3 days (Fig. 5Go). Sections were counterstained with hematoxylin-eosin.



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  		Figure 3. Distribution of SR-BI mRNA in rat tissues. a, SR-BI mRNA measured by RPA in 50 µg total RNA from different rat tissues, as described in Materials and Methods. The bands protected by the SR-BI probe and the ß-actin probe were quantified with a Phosphor-Imager, and for each tissue, SR-BI expression was determined as the SR-BI mRNA/ß-actin mRNA ratio. b, Localization of SR-BI transcripts in rat ovary (arrows indicate corpora lutea), adrenal gland, and liver, determined by in situ hybridization and visualized by PhosphorImager with SR-BI antisense (upper panel) and sense (lower panel) probes, as described in Materials and Methods.

 


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  		Figure 5. SR-BI mRNA distribution in ovaries from untreated immature rats and from immature rats stimulated with PMSG and hCG, determined by in situ hybridization. Shown are hematoxylin/eosin-stained sections (a–d; brightfield microscopy) of ovaries subjected to in situ hybridization with SR-BI antisense probe (e–j; darkfield, low magnification) or SR-BI sense probe (i–l; darkfield, low magnification) and with SR-BI antisense probe (m–p: high magnification), as described in Materials and Methods. Indicated are a follicle (F), granulosa cells (GC), thecal cells (Tc), and corpus luteum (CL).

 
Chromosome mapping
The pMJ4:126–18 plasmid, corresponding to about 1.4 kilobases of the rat cDNA, and a 2.4-kilobase sequence-verified EST clone, corresponding to human CLA-1 cDNA (dbEST Id 283327; Genomesystems, St. Louis, MO), were used as probes for FISH analysis. The probes were labeled by nick translation with digoxigenin-11-deoxy-UTP (Boehringer Mannheim, Mannheim, Germany). FISH was performed essentially according to the method of Pinkel et al. (25) as described in detail by Helou et al. (26). For mapping of the rat gene, FISH analysis was performed on metaphases from the rat FR1D fibroblastoid cell line. For mapping of the human SR-BI homolog, the probe was mixed with an HSA12 {alpha}-satellite probe (D12Z3; Appligene/Oncor, Illkirch, France) before hybridization to human peripheral blood lymphocyte metaphases.

Statistical analysis
The differences between treatment groups were analyzed by ANOVA with correction for repeated measurements (Scheffe’s F test), using the StatView statistical analysis software (Abacus Concepts, Berkeley, CA). Differences with P < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Analysis of rat SR-BI cDNA
To obtain the rat SR-BI cDNA, RT-PCR was performed on rat liver RNA using degenerate primers based on the mouse and hamster SR-BI cDNA sequences (14, 24). The resulting cDNA sequence contained an open reading frame of 1527 bp corresponding to 509 amino acids (Fig. 1Go; GenBank accession no. U76205). The predicted protein contained 8 cysteins and 11 potential N-glycosylation sites and displayed 90%, 88%, and 78% identity to the mouse, hamster and human homologs (GenBank accession no. U37799, U11453, and Z22555), respectively. Two hydrophobic regions, previously predicted for the hamster and human homologs (24, 27) and anticipated to serve as membrane-spanning segments of the protein, were detected in the predicted rat SR-BI protein using the algorithm of Kyle and Doolittle (data not shown). The predicted protein contained potential intracellular phosphorylation sites for protein kinase C (Ser4 and Ser477) and protein kinase A (Ser481), a leucine zipper domain, and a peroxisomal targeting sequence (PTS1), all of which were conserved among species (Fig. 1Go).



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  		Figure 1. Rat SR-BI cDNA nucleotide sequence (lowercase letters), its predicted amino acid sequence (uppercase letters), and comparison with the mouse, hamster, and human SR-BI homologs. Putative transmembrane regions are underlined by black bars; light-hatched regions represent species differences in the predicted amino acid sequences; boxed regions indicate potential N-glycosylation sites; black regions indicate leucine residues of a putative leucine zipper domain (spanning amino acids 427–455); the dark-hatched region indicates a putative peroxisomal targeting sequence (PTS1).

 
Chromosomal localization
The chromosomal locations of the rat SR-BI gene and its human homolog, the CD36- and LIMPII analogous-1 (CLA-1) gene, were determined by FISH (Fig. 2Go). The rat gene was mapped to the borderline between bands q15 and q16 on rat chromosome 12 (RNO12q15–16). The rat locus was designated Srb1 (scavenger receptor B1) in accordance with the official rat genetic nomenclature recommendations (28). The corresponding human locus (Genome Database locus designation CD36L1) has been assigned to chromosome 12 (HSA12), as determined by somatic cell hybrids (28). Comparative mapping shows that a small conserved chromosome region between HSA12 and RNO12, which includes three other loci (NOS1, POLE, and TCF1), is located in HSA12q24. Thus, it could be predicted that the human SR-BI homolog would map to this region, and, in fact, FISH analysis with the 2368-bp human CLA-1 EST clone mapped to HSA12q24.31-q24.32 (Fig. 2bGo).



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  		Figure 2. a, Chromosomal mapping of the rat Srb1 gene by FISH. Signals are seen on both chromatids of both copies of RNO12 (arrows), and the Srb1 gene can be assigned to RNO12q15–16. b, Mapping of the homologous human gene. There are strong signal from HSA12-specific {alpha}-satellite at the centromeres and signals from the CLA-1 clone at HSA12q24.31-q24.32 (arrows). c, Chromosomal diagrams of RNO12 (left) and HSA12 (right) showing the positions of the SR-BI genes in the two species.

 
Tissue distribution of SR-BI messenger RNA (mRNA)
Figure 3Go shows the expression of the SR-BI gene in various rat tissues. High levels of SR-BI mRNA were detected by RPA in the adrenal gland, ovary, and liver, whereas expression was low, but detectable, in several other tissues, including small intestine, adipose tissue, and lung (Fig. 3aGo). In the ovary, adrenal gland, and liver, SR-BI gene expression was also determined by in situ hybridization (Fig. 3bGo). In the ovary, the expression of the SR-BI gene was high in corpus luteum compared with that in the surrounding tissue, and in the adrenal gland high expression was detected in the cortex. In contrast, in the liver, SR-BI expression was evenly dispersed throughout the parenchyma.

Characterization of SR-BI gene expression in rat ovary
The ovary is a dynamic tissue with simultaneous growth, differentiation, and induction of apoptosis (29). To study the regulation of SR-BI gene expression in the ovary, immature rats (25 days old) were injected with 10 IU PMSG (to induce follicular development) or with 10 IU PMSG followed by 25 IU hCG 2 days later (to induce ovulation). In immature rats in which follicular development had been induced by PMSG treatment, ovarian SR-BI gene expression was not significantly different from that in untreated immature control rats or that analyzed 12 h post-hCG administration (Fig. 4Go). In contrast, there was a small, but significant, increase in ovarian SR-BI mRNA levels in the rats treated with a combination of PMSG and hCG analyzed 48 h post-hCG administration (Fig. 4Go). To determine which compartments in the ovary were responsible for this increase, SR-BI gene expression was analyzed by in situ hybridization (Fig. 5Go). In the immature ovary, a strong hybridization signal was detected in thecal cells and interstitial cells, whereas the signal was barely above background in granulosa cells of preantral follicles (Fig. 5Go, e and m). In ovaries obtained from PMSG-primed immature rats, high SR-BI gene expression was detected in the thecal cell layer of preovulatory follicles (Fig. 5Go, f and n). In preovulatory PMSG-primed ovaries stimulated with hCG for 12 h, the cellular distribution of SR-BI mRNA was similar to that in the ovaries from rats primed with PMSG only, with a strong signal in thecal cells (Fig. 5Go, g and o). In ovaries from PMSG-primed rats stimulated with hCG for 48 h, the hybridization signal was strong in corpus luteum and in thecal cells of large antral follicles (Fig. 5Go, h and p; see also Fig. 4bGo). Granulosa cells of all stages of follicular development showed a weak hybridization signal. Therefore, we also analyzed the level of expression in isolated granulosa cells compared with the residual ovarian tissue, comprising thecal and interstitial cells, of the same ovaries by means of RPA (Fig. 6Go). The level of expression in granulosa cells was low compared with that in residual ovarian tissue of PMSG-stimulated ovaries.



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  		Figure 4. SR-BI gene expression in rat ovary. SR-BI mRNA was measured in ovaries from untreated immature rats (control) and in ovaries from immature rats treated with PMSG or with a combination of PMSG and hCG (n = 5 for all groups), as described in Materials and Methods. SR-BI mRNA was measured by RPA in 50 µg total RNA. The bands protected by the SR-BI probe and the ß-actin probe were quantified with a PhosphorImager. There was a significant increase in ovarian SR-BI mRNA levels in the rats treated with a combination of PMSG and hCG 48 h post-hCG administration, as analyzed by ANOVA (*, P < 0.05) with correction for repeated measurements.

 


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  		Figure 6. SR-BI gene expression in isolated granulosa cells (GC) and residual ovarian tissue (ROv) of the same PMSG-stimulated rat ovary. SR-BI mRNA was measured by RPA in 50 µg total RNA. The bands protected by the SR-BI probe and the ß-actin probe were quantified with a PhosphorImager.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is well known that plasma levels of HDL are inversely correlated to the risk of developing cardiovascular disease. However, little is known about the molecular mechanism regulating the cellular uptake of HDL cholesterol. SR-BI is the first HDL receptor to be identified at the molecular level, and it may provide an important tool for elucidating the mechanisms involved in cellular uptake and metabolism of HDL cholesterol. In this study we have started to characterize the rat homolog of SR-BI.

SR-BI is highly conserved between species, and the rat receptor displayed 90%, 88%, and 78% identity to the mouse, hamster, and human homologs, respectively. Furthermore, chromosomal localization of rat SR-BI and the human CLA-1 genes confirmed that they represent homologous genes in different species. Sequence analysis of rat SR-BI identified two novel motifs in the predicted protein, a C-terminal peroxisomal targeting sequence (PTS1) and a leucine zipper motif. Alignment of the rat, mouse, hamster, and human SR-BI homologs showed that the these motifs were conserved, with the exception of Met441 in the leucine zipper motif of the human homolog. PTS1 is recognized by a specific receptor, the PTS1 import receptor, which directs PTS1-containing proteins to the peroxisome (30, 31). The peroxisome is the subcellular site for ß-oxidation, synthesis of bile acids and cholesterol, and degradation of the side-chain of cholesterol (32). Cholesterol from HDL is preferentially secreted into bile, relative to cholesterol from other sources (33), and overexpression of SR-BI has been shown to increase biliary cholesterol (20). Therefore, the presence of a PST1 motif in the predicted SR-BI protein further supports the concept that it participates in cholesterol and bile acid metabolism.

Analysis of the rat SR-BI sequence also revealed a leucine zipper domain (34) that was present in the mouse, hamster, and human SR-BI homologs as well. This opens the possibility that SR-BI may form homo- or heterodimers. Leucine zippers are a well characterized dimerization domain in the bZIP family of transcription factors, which includes the Fos, Jun, and CREM family of proteins (34, 35, 36). This motif is not restricted to transcription factors; instead, putative leucine zippers have been found in the outer dense fiber protein I (ODF-I) (37), ODF-84 (38), protein kinases (39, 40, 41), interleukin-2 receptors (42), tyrosine hydroxylase (43), human DNA topoisomerase II (44), microtubule-associated proteins (45), and a viral envelope protein (46, 47). The leucine zipper domain in ODF-I is involved in homodimerization; however, this interaction is weak. Instead, this domain appears to be important for the formation of a heterodimer between ODF-I and ODF-84. These studies indicate that the region containing a leucine zipper domain may be of importance for determining the specificity of dimer formation. Analysis of SR-BI by Western blotting has revealed an additional band approximately twice the size of that expected for SR-BI (48). Although caveolin has been shown to colocalize and coprecipitate with SR-BI (49), a heterodimer of these proteins would not be expected to comigrate with this band. Future studies are needed to determine whether the predicted leucine zipper domain in SR-BI is functional and whether it is involved in homodimerization or heterodimerization with an as yet unidentified protein.

The SR-BIs and their related genes, CD36 and LIMP II, have been predicted to encode proteins with two transmembrane domains (24, 50, 51) generating two intracellular and one large glycosylated extracellular domain. We detected a similar pattern in a hydropathy plot of rat SR-BI, using the algorithm of Kyle and Doolittle (data not shown). Furthermore, as for the related genes, all of the N-glycosylation signals in rat SR-BI were found in the predicted extracellular domain. Detailed studies of the posttranslational modifications of murine SR-BI have shown that at least five of these sites are, in fact, glycosylated (49). Furthermore, the intracellular domain of SR-BI contains conserved potential phosphorylation sites for protein kinase C (Ser4 and Ser477) (52) and cAMP/cGMP-dependent protein kinases (Ser481) (53) that may be involved in the regulation of receptor activity.

The rat SR-BI probe mapped to the borderline between bands q15 and q16 on rat chromosome 12 (RNO12q15–16). Interestingly, a region near the end of the long arm (HSA12q24) is known to contain three genes (NOS1, POLE, and TCF1) with homologs on RNO12. Therefore, it could be predicted that the human SR-BI gene is located in this region. This is also in agreement with the previous assignment of the human SR-BI homolog, CLA-1, to chromosome 12, using PCR with hamster-human hybrid cell lines as templates (54). Indeed, our FISH analysis mapped the SR-BI gene to human chromosome locus 12q24.31-q24.32. These data define SR-BI as an additional member of the conserved synteny group retained on rat chromosome 12 and human chromosome 12q24.3. The TCF1 and NOS1 genes have previously been located to mouse chromosome 5. Thus, based on the locations of mouse Tcf1 and Nos1 genes on chromosome 5 (MMU5) at centimorgan positions 65.0 and 70.0, respectively, it can be predicted that the mouse Srb1 gene homolog will map to the same region on MMU5. The genomic colocalization of the rat and human SR-BI homologs to a small chromosomal segment conserved between species is indicative of the value of cross-species mapping of chromosomes. The genes encoding the structurally related CD36 and LIMPII have been mapped to chromosomes 7 and 4, respectively, indicating that they have diverged early in evolution. No human syndrome with deficiencies in steroid production or with cardiovascular disease was found when human chromosomal locus 12q24 was searched for human syndromes at the On-Line Mendelian Inheritance in Man database (OMIM, Center for Medical Genetics, Johns Hopkins University, Baltimore, MD; 1996; World Wide Web URL: http://www.ncbi.nlm.nih.gov/Omim/).

SR-BI mRNA was most abundant in thecal cells and corpus luteum in ovary and adrenal cortex. These are tissues that have selective uptake of HDL cholesterol (8, 9, 12, 55), indicating a role of SR-BI in the uptake of HDL cholesterol (24) as a substrate to steroid-producing organs. The regulation and tissue distribution of SR-BI indicate that it is a functional receptor for HDL (14, 24, 48, 56). The distribution of SR-BI mRNA expression is in agreement with the localization of immunoreactive SR-BI (48).

We detected a significant increase in SR-BI mRNA expression (~40%) in ovaries from rats stimulated with PMSG and hCG when analyzed 48 h post-hCG administration. Presumably, this would reflect the increased need for cholesterol substrate in the ovary required to maintain high levels of steroid production. The regulation and distribution of SR-BI transcripts in the ovary, i.e. high expression in luteal cells, moderate expression in thecal cells, and low expression in granulosa cells, are compatible with previous immunohistochemical studies (48). Furthermore, this is in line with the decrease in cholesterol ester content in these compartments seen in apo A-I knock-out mice compared with that in normal mice (17). Landschulz and co-workers demonstrated an increase in SR-BI protein expression in corpus luteum and a parallel decrease in expression in surrounding thecal cell layers in response to estrogen treatment (48). Our studies show a strong signal of SR-BI mRNA expression in corpus luteum and a modest decrease of the signal in interstitial ovarian tissue as a result of hCG-induced luteinization of the PMSG-primed ovary.

Although hCG induced a significant increase in SR-BI gene expression, it is possible that this is an indirect effect. LH stimulates steroidogenesis and depletes cholesterol esters in rat luteal cells (57). The decrease in intracellular cholesterol content could be an important regulator of SR-BI expression. This is supported by a recent study by Wang and co-workers demonstrating that SR-BI expression is up-regulated when cholesterol stores are depleted (56). This is independent of whether it is caused by decreased uptake of cholesterol or increased cholesterol utilization. SR-BI expression is up-regulated in steroidogenic organs by estrogen (48), hCG (48), and ACTH (58) and in response to stress (56).

We conclude that the cellular distribution of SR-BI mRNA in ovary and adrenal gland is consistent with a role of SR-BI in mediating the uptake of HDL cholesterol in these tissues. The identification of a putative leucine zipper and a peroxisomal targeting sequence may be of importance for elucidating the function of SR-BI as a HDL receptor.


   Acknowledgments
 
We thank Ulla Karlsson, Majlis Hermansson, and Britt Gabrielsson at the Research Center for Endocrinology and Metabolism for technical advice.


   Footnotes
 
1 This work was supported by Swedish Medical Research Council Grants 11285, 11331, 11502, and 11576 (to B.C. and L.C.) and Grants 10380 and 11134 (to H.B.); the Swedish Medical Association (to M.J.); the Göteborg Medical Association (to M.J.); and the Swedish Heart-Lung Foundation (to M.J.). Back

Received July 31, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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