J. Anim Sci. 2006. 84:2887-2894. doi:10.2527/jas.2006-042
© 2006 American Society of Animal Science
Identification of the bovine cholesterol efflux regulatory protein ABCA1 and its expression in various tissues1
C. Farke,
E. Viturro,
H. H. D. Meyer and
C. Albrecht2,3
Physiology Weihenstephan, Technical University Munich, 85354 Freising, Germany
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Abstract
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The ATP-binding cassette transporter A1 (ABCA1) is known to play a significant role in cellular export of phospholipids and cholesterol in humans. The ABCA1 transporter might also play a crucial role in cellular cholesterol homeostasis in the cow or in the transfer of cholesterol into the milk, but its presence and tissue distribution in the bovine is unknown. Therefore, we studied the expression and distribution of the bovine ABCA1 transporter using quantitative PCR and sequenced the entire ABCA1 coding region. In addition, the proximal promoter was identified and screened for regulatory elements. Concordant with data from other mammalian species, bovine ABCA1 mRNA was expressed and detected in all tissues tested. The highest expression levels were detected in lung, esophagus, uterus, spleen, and muscle. Sequence analysis revealed that the open reading frame of this gene consists of 6,786 bases and encodes for a protein of 2,261 AA with a predicted molecular weight of 254 kDa. The deduced bovine ABCA1 protein shows the highest AA sequence homology with human (94%), mouse (93%), rat (92%), and chicken (85%). Analysis of the putative ABCA1 promoter region revealed potential transcription factor binding sites associated with ABCA1 transcription and lipid metabolism. This work could open new avenues for elucidating a potential role of ABCA1 in sterol homeostasis in the bovine organism.
Key Words: ABCA1 • ATP-binding cassette transporter • Bos taurus • cattle • quantitative PCR • sterol homeostasis
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INTRODUCTION
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The ATP-binding cassette (ABC) transporter family represents the largest family of transmembrane proteins. These proteins bind ATP and use the energy to drive the transport of a variety of substrates across cellular membranes (Higgins, 1992
; Childs and Ling, 1994; Dean and Allikmets, 1995). Most of the known functions of eukaryotic ABC transporters involve the shuttling of hydrophobic compounds within the cell as part of a metabolic process or outside the cell for transport to other organs, or secretion from the body.
Mutations in a number of ABC genes are responsible for human inherited diseases. The ABCA1 transporter is involved in disorders concerning cholesterol disposition, such as Tangier disease and familial high-density lipoprotein deficiency (Brooks-Wilson et al., 1999; Albrecht et al., 2004a). With the discovery that mutations in the ABCA1 gene were causal to Tangier disease, a rare hereditary disease that severely impairs the reverse cholesterol transport (Bodzioch et al., 1999; Brooks-Wilson et al., 1999; Rust et al., 1999), the physiological importance of this protein was recognized. Moreover, ABCA1 has been implicated in atherosclerosis (Albrecht et al., 2004b; Soumian et al., 2005; Oram and Heinecke, 2005) and Scott syndrome, a rare bleeding disorder (Albrecht et al., 2005).
Whereas ABC transporters play a considerable role in hereditary human diseases, only scarce information is available about their expression and function in food-producing animals. Only 5 ABC proteins have been identified in Bos taurus (Ambagala et al., 2002; Taguchi et al., 2002; Beharry et al., 2004; Vitarro et al., 2006), and their function remains unknown.
In the current study, the expression of ABCA1 was demonstrated for Bos taurus, and its sequence and tissue distribution were characterized in this species. Special interest was placed on characteristics in the proximal promoter and coding region that may indicate a potential role of the bovine ABCA1 in lipid homeostasis in bovine cells or tissues.
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MATERIALS AND METHODS
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This study was performed according to the requirements of the Bavarian state animal welfare committee.
RNA Tissue Bank and Reverse Transcription
A bovine, noncommercial tissue bank composed of 16 tissues was obtained after slaughter from 1 healthy adult lactating Holstein-Friesian cow without previous history of disease or drug treatment. Total RNA was isolated using the RNeasy Mini Kit or, for mammary gland tissue, the RNeasy Lipid Tissue Mini Kit (Qiagen GmbH, Hilden, Germany). For fibrous tissues such as heart, tongue, and muscle, a proteinase K step was added after homogenization to increase the RNA yield. The RNA was quantified at 260 nm in a spectrophotometer (BioPhotometer, Eppendorf, Hamburg, Germany), obtaining an OD 260/280 ratio of 1.7 to 2.0 for all samples.
Synthesis of first strand cDNA was performed using 1 µg of total RNA and 200 U of SuperScript III reverse transcription (Invitrogen, Karlsruhe, Germany). The reverse transcription reaction was carried out according to the manufacturer in a 20-µL reaction volume in a PCR thermocycler (Biometra, Goettingen, Germany) and was achieved by successive incubations at 25°C for 5 min and 50°C for 45 min, finishing with enzyme inactivation at 70°C for 15 min.
PCR and Sequence Analysis
The cDNA, stored at –20°C, served as a template for PCR. To screen for evolutionarily conserved sequences within the coding regions, gene sequences from rat, mouse, and human were compared by linear sequence alignment strategies using HUSAR software (DKFZ, Heidelberg, Germany). Primers (Table 1) were designed within the most conserved regions using Primer3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi; Rozen and Skaletsky, 2000) and used in various combinations to amplify overlapping cDNA fragments of 0.3 to 1.0 kb size.
The PCR reactions were performed in a PCR thermocycler (Biometra) and contained 100 ng of cDNA, 10x PCR reaction buffer, 0.4 µM of forward and reverse primers (Metabion, Martinsried, Germany), 200 µM of dNTP (ABgene, Hamburg, Germany), and 1.25 U of the proof-reading enzyme Pfu DNA-Polymerase (Promega, Madison, WI), in a final volume of 50 µL. The PCR products were subjected to gel electrophoresis in 1 to 2%-agarose gels containing 1 µg of ethidium bromide/mL. The DNA fragments were extracted using the Wizard SV Gel and PCR Clean-Up System (Promega), and both strands were commercially sequenced (Agowa, Berlin, Germany).
Rapid Amplification of cDNA Ends (RACE)
To determine the 5' and 3' end of the ABCA1 mRNA, RACE was performed using the 5'/3'RACE Kit, second Generation (Roche Diagnostics, Mannheim, Germany) and total RNA from bovine liver as a template. The 5' RACE fragment was generated using an oligo dT-anchor primer (provided in the kit) and the gene-specific primer 5'-CCT CAG CAT CTT GTC CAC AG-3'. For generating the 3' RACE fragment, the oligo dT-anchor primer and the gene-specific primer 5'-TGA AGC TCT CTG CAC TAG GAT G-3' were combined. The amplified products were commercially sequenced (Medigenomix, Martinsried, Germany).
Promoter Analysis
Due to the high degree of identity that has been reported for the human and mouse ABCA1 promoter regions (Santamarina-Fojo et al., 2000), the human ABCA1 promoter sequence was compared by linear sequence alignment strategies to Baylor Bovine Data (http://www.hgsc.bcm.tmc.edu/blast/?organism=Btaurus) to identify the bovine analogue of the promoter region. According to bovine Contig 222145, specific primers were designed and used with bovine liver genomic DNA. The resulting overlapping fragments were sequenced (Medigenomix) and assembled.
The putative ABCA1 promoter sequence was analyzed for potential transcription factor (TF)-binding sites using MatInspector software (http://www.genomatix.de) and MOTIF software (http://motif.genome.jp).
Real-Time PCR
Quantitative reverse-transcription PCR of ABCA1 mRNA in bovine tissues was carried out using LightCycler DNA Master SYBR Green technology (Roche Diagnostics, Mannheim, Germany). Primer pairs (Table 2) were designed covering 2 exon boundaries to avoid amplification of genomic DNA. The PCR reactions were performed in a final volume of 10 µL, using 1 µL of the LC FastStart DNA Master SYBR Green I (Roche Diagnostics), 4 pmol of each primer, 3 mM MgCl2, and 50 ng of cDNA. Before amplification, an initial high-temperature incubation step was performed to activate the DNA polymerase and to ensure complete denaturation of cDNA. All PCR reactions were composed of 40 cycles. Product-specific PCR conditions are listed in Table 3.
Amplified products underwent melting curve analysis after the last cycle to specify the integrity of amplification. Data were analyzed using the second Derivate Maximum calculation described in the LightCycler Software 3.5. All runs included a negative cDNA control consisting of PCR-grade water, and each sample was measured in duplicate. To minimize any bias related to a potential differential tissue expression of genes used for data normalization, 4 housekeeping genes were included in the analysis [glycerol-3-phosphate dehydrogenase, ß-actin, ubiquitin, and 18S, see Tables 2
and 3]. The ABCA1 mRNA levels were expressed relative to the mean of the 4 housekeeping genes and calculated as fold-expression compared with bovine liver.
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RESULTS AND DISCUSSION
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ABCA1 cDNA and Predicted Polypeptide Structure
By amplification and sequencing of overlapping PCR fragments, an 8,893-bp cDNA containing the complete coding region of the bovine ABCA1 gene was obtained. The open reading frame comprises 6,786 bp and encodes for a 2,261 AA polypeptide with a predicted molecular weight of 254 kDa (Figure 1). The complete bovine ABCA1 cDNA and AA sequence has been deposited within the GenBank Database (Accession No. DQ059505). The deduced protein is a full-size ABC transporter with 2 transmembrane domains and 2 nucleotide binding domains, identified by the conserved ATP-binding cassettes including Walker A and Walker B motifs and signature sequences (Figure 1). Homology search with the predicted bovine ABCA1 AA sequence revealed the greatest identity to human (94%), mouse (93%), rat (92%), and chicken ABCA1 (85%).
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Figure 1. Alignment of bovine (bABCA1, Accession No. AAY53813) and human (hABCA1, Accession No. AF285167) ABCA1. Amino acid sequences begin at position 900, close to the first ATP-binding-cassette motif. Walker A; Walker B; signature sequence C motifs; and proline, glutamic acid, serine, and threonine (PEST) sequences are bold and shaded. Differences in the AA sequences are shaded.
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It has been reported that in some human cells, such as skin fibroblasts, leukemia T-cells, endothelial and smooth muscle cells, as well as hepatoma cells, 2 ABCA1 gene transcripts, 1 presumably devoid of function, have been observed (Bellincampi et al., 2001). The PCR amplification of bovine cDNA with specific primers in this region could not confirm alternative splicing between exons 3 and 5 for Bos taurus in any tissue tested.
Recently it has been shown that in mouse ABCA1 a sequence rich in proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST sequence) enhances the degradation of ABCA1 by calpain protease and thus controls the cell surface concentration and cholesterol efflux activity of ABCA1 (Wang et al., 2003). The PEST sequences are found in many proteins undergoing rapid turnover (Rechsteiner and Rogers, 1996). Using the software PESTfind (https://emb1.bcc.univie.ac.at), we identified a conserved potential PEST sequence with a PEST score of +16.22 in bovine ABCA1 (Figure 2). According to the very high homology between other mammalian and bovine ABCA1 PEST sequences, it is likely that they all fulfill similar physiological functions and contribute to the regulation of ABCA1 degradation.
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Figure 2. Alignment of the ABCA1 sequences rich in proline, glutamic acid, serine, and threonine (PEST) across species. Dots indicate identical AA residues compared with bovine ABCA1.
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Promoter Region of the Bovine ABCA1 Gene
Analysis of the proximal promoter region revealed a high degree of conservation between the bovine and human ABCA1 genes. The bovine promoter sequence has been deposited at the GenBank database (Accession No. DQ142640).
The genomic region upstream of the transcription initiation site of ABCA1 (Figure 3) contains several putative elements for transcriptional regulation. Analysis of the bovine ABCA1 promoter identified multiple motifs that were strongly conserved between human and bovine sequences, pointing to important biological functions. Some of these potential transcription factor binding sites are also present in the promoter of receptors involved in lipid metabolism, including the low density lipoprotein receptor, scavenger receptor A, scavenger receptor class-B type I (SR-BI), and CD36, another member of the class-B scavenger receptor family. These receptors include binding motifs for SP1, activator protein 1 (AP1), sex determining region Y (SRY), and nuclear factor kappa-B (NF-
B; Armesilla and Vega, 1994; Cao et al., 1997; Valledor et al., 1998). A TATA box and CAAT box motif were identified at –31 and –569 bp upstream of the transcriptional start site, respectively. In addition, we identified an E-box motif at position –148 and the recognition element for the basic helix-loop-helix leucine zipper containing proteins (position –223), such as the sterol regulatory element binding proteins, which are binding sites for sterol regulation (Brown and Goldstein, 1997). Similar E-box motifs have been reported in the promoter for SR-BI (Cao et al., 1997; Lopez and McLean, 1999), fatty acid synthase (Magana et al., 2000), human CD36 (Armesilla and Vega, 1994), and the low density lipoprotein receptor (Brown and Goldstein, 1997). These predicted features are consistent with the promoter region of other members of the ABCA subfamily, such as ABCA2, ABCA7, and ABCA13 (Broccardo et al., 2001; Kaminski et al., 2001; Barros et al., 2003). The high degree of similarity between motifs in the human and bovine ABCA1 promoter structure strongly suggests a role for ABCA1 in bovine sterol homeostasis.
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Figure 3. Putative proximal promoter sequence of the ABCA1 gene with predicted transcription factor binding sites (shaded). TATA box, E-box, and CAAT box motifs are bold and underlined. The putative start of exon 1, according to the human sequence (NM_005502), is indicated by an arrow and shown in bold. The translational start site (ATG) is located on exon 2 (not shown in the figure). HNF3ß = hepatocyte nuclear factor 3 beta; SRY = sex determining region Y; SOX5 = SRY-box 5; NF-B = nuclear factor kappa-B; SREBP = sterol regulatory element binding protein; AP = adaptor-related protein complex; STAT = signal transducer and activator of transcription; ZNF202 = zinc finger protein 202; and LXR = liver X receptor.
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Tissue-Specific Expression of Bovine ABCA1
The ABCA1 transcript was detected in all tissues of Bos taurus that were analyzed. These tissues are mainly involved in barrier function (lung, intestine), reproductive function (uterus), and metabolic function (liver). The greatest expression level was observed in lung (Figure 4). These results resemble those of Kielar et al. (2001) and Langmann et al. (2003) in human tissues. The primary function of ABCA1 in human lung might be to modulate lipid pools in alveolary epithelial cells (Agassandian et al., 2004). An alternative assumption is that ABCA1 in human lung takes part in cholesterol homeostasis and supports the reverse transport of cholesterol (Santamarina-Fojo et al., 2001).
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Figure 4. Quantitative analysis of ABCA1 mRNA in bovine tissues. Bars represent relative quantification calculated as fold-expression compared with liver (cross-hatched bar). Values were normalized to the mean of 4 housekeeping genes (glycerol-3-phosphate dehydrogenase, ß-Actin, Ubiquitin, and 18S).
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High expression levels were also found in esophagus, uterus, spleen, and muscle (Figure 4), which is partly in agreement with Langmann et al. (2003). Moderate levels of expression were detected for liver, tongue, gastric tissues, cecum, jejunum, heart, and lymph nodes, whereas, congruent with distribution patterns in human tissues, low expression was observed in colon and kidney (Figure 4). The function of intestinal ABCA1 is likely to generate HDL particles that transport dietary cholesterol to the liver. In humans, the resecretion of cholesterol in the intestine is mediated by 2 other intestinal ABC transporters (ABCG5 and ABCG8; Oram and Heinecke, 2005), which could explain the comparatively low distribution of ABCA1 in these tissues. However, in view of the markedly enhanced plasma concentration of cholesterol in cows fed fat (Blum et al., 1985; Bruckmaier et al., 1998), it would be interesting to study the expression and function of the ABCA1 transporter under these feeding conditions. It is likely that the function of ABCA1 in kidney may be to maintain normal cholesterol homeostasis and protect against hyperlipidemic renal disease (Wu et al., 2004). The detection of ABCA1 in the mammary gland might indicate a potential role of ABCA1 in the transfer of cholesterol into the milk, a hypothesis that should be investigated in further studies. Moreover, studies using in situ hybridization techniques or immunohistochemistry should be performed to determine the cellular and subcellular localization of the bovine ABCA1 transporter in various tissues.
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IMPLICATIONS
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We report the identification and characterization of bovine ABCA1 cDNA, an adenosine triphosphate-binding cassette transporter highly conserved in human, mouse, rat, and chicken. This is supported by 1) the cDNA, which shows 90% sequence homology to the human sequence and 2) the deduced ABCA1 protein, which exhibits 94% homology to the human ABCA1 protein. The deduced protein is a full-size adenosine triphosphate-binding cassette transporter with ubiquitous mRNA tissue expression. The high degree of similarity to human ABCA1 in protein sequence, sequence motifs, promoter structure, and expression levels strongly suggests an analogous role of both transporters in sterol homeostasis. Additional studies on substrate specificity and protein localization on the cellular level are needed to further elucidate the physiological role of ABCA1 in Bos taurus.
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Footnotes
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1 We thank Livia Blank, Johanna Panitz, and Tamara Stelzl for their collaboration in the laboratory work. This study was supported by grants from the Vereinigung zur Förderung der Milchwissenschaftlichen Forschung (Germany) and from the Leonhard-Lorenz-Stiftung (Germany). 
3 Current address: Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland.
2 Corresponding author: Christiane.Albrecht{at}wzw.tum.de
Received for publication January 24, 2006.
Accepted for publication May 11, 2006.
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Abstract
INTRODUCTION
