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Institute of Aquaculture, University of Stirling, Stirling FK9 4LA, UK
1 National Agricultural Research Foundation, Fisheries Research Institute, Nea Peramos, 64007 Kavala, Greece
(Requests for offprints should be addressed to M J Leaver; Email: mjl1{at}stir.ac.uk)
(M Tariq Ezaz is now at Research School of Biological Sciences, Australian National University, Canberra, Australian Capital Territory 0200, Australia)
(S Fontagne is now at INRA, 64310 Saint-Pee sur Nivelle, France)
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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, PPARß (also known as PPAR
), and PPAR
, is present (Michalik & Wahli 1999). The role of PPAR is hypothesized to be primarily in controlling the reversible induction of ß-oxidation in specific tissues, especially liver, as a response to changing energy requirements and nutritional status. The evidence for this comes most directly from rodents, where PPAR is expressed in cells with high catabolic rates of fatty acid oxidation, such as hepatocytes, cardiomyocytes, kidney proximal tubules, and intestinal mucosa (Escher et al. 2001). Indeed, PPAR-null mice are incapable of upregulating fatty acid oxidation during fasting (Kersten et al. 1999, Leone et al. 1999). In contrast, mammalian PPAR is considered to play a critical role in fat accumulation, particularly in adipocytes and in lipid-accumulating macrophages (Rosen & Speigelman 2001). The role of PPARß is less well understood. Various studies suggest that PPARß has a role in the global control of lipid homeostasis in mammals. It is moderately activated by a range of unsaturated fatty acids (Forman et al. 1997) and has a broad tissue expression profile (Escher et al. 2001). PPARß-null mice show reduced adipose stores (Peters et al. 2000), which cannot be explained by adipose-specific PPARß deficiency (Barak et al. 2002, Wang et al. 2003). Furthermore, in the absence of the ligand, PPARß can act as a repressor of PPAR and PPAR action (Shi et al. 2002). Similarly, in the cell overexpression systems and in the absence of activating ligand, PPARß can downregulate the genes involved in the lipid and energy metabolism (Tachibana et al. 2005). Recently, highly specific and potent synthetic ligands for mammalian PPARß have been developed. Treatment of animals with these compounds has demonstrated that ligand-activated PPARß directly controls lipid utilization through upregulation of genes involved in ß-oxidation and energy uncoupling in various tissues (Dressel et al. 2003, Tanaka et al. 2003, Wang et al. 2003, Tachibana et al. 2005). In consequence, PPARß ligands can have beneficial effects in correcting dyslipodemic states in various animal disease models. Thus, PPARß ligands are now receiving considerable attention as potential pharmaceuticals for the treatment of a variety of human diseases associated with dyslipidemia (Desvergne et al. 2004). In addition to functioning as a regulator of energy metabolism, PPARß has also been shown to have significant roles in the control of cellular proliferation and differentiation. Studies on PPARß-null mice have indicated the PPARß functions in skin wound healing (Michalik et al. 2001), keratinocyte differentiation (Schmuth et al. 2002, Kim et al. 2006) in apoptosis (Di-Poi et al. 2002), and skin and colon carcinogenesis (Harman et al. 2004, Kim et al. 2004).
Despite these developments, bona fide endogenous ligands for PPARß have still not been conclusively defined and the precise role of PPARß in lipid and energy metabolism, and how this relates to PPARß function in cellular differentiation and proliferation, is not yet understood. The study of PPARs in lower vertebrates such as fish offers an opportunity to compare expression, define common ligands, and infer common functions across vertebrates, thus informing studies on PPARs in humans. Recently, a study on two members of a major fish clade, the Perciformes, reported the identification and characterization of homologs of PPAR, ß, and (Leaver et al. 2005). Comparison of these gene sequences with information from the pufferfish (Takifugu rubripides and Tetraodon nigroviridis, also Perciformes) genome-sequencing projects suggested that these fishes possessed a single PPARß gene and that they shared many of the features of their mammalian counterpart. However, examination of the zebrafish genome database indicated that there are two PPARß genes in this Cypriniform species. Consequently, the exact number of genes and/or the presence of distinct PPAR isoforms in fish are yet to be determined. Here, we show that multiple PPARß genes are present in Atlantic salmon, a commercially important member of a third major fish clade, the Salmoniformes. Two of these gene products are demonstrated to differ in tissue expression profile and transactivation properties.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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An Atlantic salmon genomic DNA library was constructed in 
FIXII (Stratagene, La Jolla, CA, USA) from DNA isolated from blood from a single individual. This library was screened with a 32P-labeled DNA probe corresponding to the ligand-binding domain (LBD) of plaice (Pleuronectes platessa) PPARß (Leaver et al. 2005). Hybridizing clones were isolated, phage DNA purified, restriction digested, and subjected to Southern blot analysis using the plaice PPARß probe. Hybridizing restriction fragments were then subcloned to plasmid vectors and sequenced using an ABI 477 autosequencer and BigDye sequencing reagents. Sequences were analyzed using Autoassembler software supplied by Applied Biosystems.
Isolation of Atlantic salmon PPARß cDNAs
Full-length cDNAs were isolated from total salmon liver RNA using reverse transcription, PCR, and RACE (SMART RACE system, BD Clontech, Oxford, UK). Gene-specific primers (P1, P2, and P3; Fig. 1
and Table 1) were directed to the regions immediately adjacent to PPARß termination codons predicted from genomic sequencing. These primers were combined in 5'-RACE PCRs with SMART liver cDNA and the SMART system universal primer. Further, RACE PCR was performed with primers synthesized to specific regions within the products arising from the first round of reactions. These primers (P4 and P5; Fig. 1 and Table 1) were used in nested PCR procedures. Finally, full-length open reading frames for salmon PPARß cDNAs were obtained using both forward and reverse gene-specific primers (P1, P6, P7, and P8; Fig. 1 and Table 1), designed from consideration of the previously isolated RACE products. All products were ligated to Escherichia coli plasmid vectors and sequenced.
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Total RNA was isolated from tissues of three Atlantic salmon (average mass=200 g) using TriReagent (Sigma). For quantitative PCR (QPCR), 1 µg total RNA was converted to cDNA using a blend of poly-dT oligonucleotide primer (25 nM) and random hexamers (75 nM), and Reverse-iT reverse transcriptase (AMV/MMuLV blend; Abgene, Epsom, Surrey, UK). QPCRs of 20 µl contained 100 nM of each primer, cDNA from the equivalent of 25 ng total RNA for PPARß reactions and from the equivalent of 0.25 ng RNA for 18S rRNA reactions. Amplicons were quantified using SYBR Green PCR mastermix (Abgene) and a Techne Quantica QPCR instrument. Cycling parameters consisted of a 15-min 95 °C soak to activate the polymerase, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min. Primers were directed to areas where the two cDNAs exhibited low nucleotide identity, either side of the junction corresponding to the first exon of the LBD of each PPAR. For ssPPARß1A, these were 5'-GACCACCAACCC-CAATGGCTCGGAT and 5'-CAGCCCATTCTCAGCCT-GGCACAAG, and for ssPPARß2A, 5'-CCCCCACCATCT TGGTGGCTCAGA and 5'-TAGACCACTCTCTGCTTG-CCACAGG. The PCR products produced from these primers under QPCR conditions were checked by gel electrophoresis and sequencing before undertaking QPCR. In each case, only the predicted products of 176 and 190 bp for ssPPARß1A and ssPPARß2A respectively, were amplified. Values for PPARß were normalized to 18S rRNA levels measured with primers 5'-CTGCCCTATCAACTTTCGATGGTACT and 5'-AA-AGTGTACTCATTCCAATTACGGGG.
Cell transfection experiments
Salmon PPARß cDNAs were ligated to pcDNA3 and used to transfect AS (derived from Atlantic salmon, epitheloid; Nicholson & Byrne 1973) cells with pCMVßgal and a reporter construct containing a PPRE from the mouse cyp4A6 promoter (Ijpenberg et al. 1997) linked to a chloramphenicol acetyltransferase (CAT) gene. AS cells were routinely grown and passaged in Dulbecco’s modified Eagle’s medium (DMEM), 10% fetal bovine serum (FBS). Prior to transfection, cells were passaged into DMEM, plus charcoal/dextran-stripped 10% FBS (Pierce, Rockford, IL, USA). Total plasmid DNA (1.5 µg) was transfected to each well of 12-well tissue culture plates using 7.5 µl Superfect reagent according to the manufacturer’s instructions (Qiagen). Twenty-four hours after transfection, cells were treated with fatty acids (100 µM; Sigma), Wy16463 (50 µM), rosiglitazone, GW501516 (10 µM; Alexis Corporation, Nottingham, UK), and L165041 (10 µM; Calbiochem, Nottingham, UK) in 5 µl ethanol. Cells were harvested 24 h after treatment, lysed in 300 µl detergent-based buffer, and CAT protein was measured using an ELISA method (Roche). ß-Galactosidase activity was measured in a microtitre plate-based assay. Briefly, 20 µl cell lysate was incubated with 130 µl PBS containing 5 mM MgCl2, 10 mM ß-mercaptoethanol, and 1.5 mM O-nitrophenyl-ß-galactoside (ONPG). After 30 min, the reaction was stopped by the addition of 75 µl of 1 M Na2CO3 and the A420 measured. CAT quantity was normalized to ß-galactosidase activity and, after subtracting mock-transfected blank values, values for each treatment were expressed relative to the ethanol control for pcDNA3 (empty vector). All treatments were performed in triplicate.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The salmon genomic library was screened with a probe corresponding to the LBD of a plaice PPARß (Leaver et al. 2005), and a total of nine distinct phage inserts were found to contain PPARß-related sequences. Assembly of the sequences from these nine inserts produced four distinct clone sets, each comprised overlapping genomic fragments. Comparisons of exon sequences corresponding to the LBD of PPARß suggested that they contained distinct sequences. Based on the genomic sequence information, oligonu-cleotide primers were designed to be specific for each PPARß sequence. Initially, primers were directed to the regions adjacent to the termination codons of each of the three gene sequences (L1, L29, and L92 clone sets; Fig. 1
). For the L1 clone set, a single cDNA was isolated (designated as ssPPARß1A), which was found to contain a full-length open reading frame for PPARß. For L92, a partial cDNA was obtained, containing only the coding region corresponding to the LBD of PPARß. This cDNA was distinct from ssPPARß1A. No PPARß cDNAs were obtained for the L29 clone set (designated as ssPPARß1B). Using the partial cDNA sequence derived from the L92 clone set, two more oligonucleotides were designed to areas within the region corresponding to the LBD. These were used in a nested 5'-RACE procedure and two distinct cDNAs were obtained. One of these cDNAs contained an open reading frame for a PPARß isoform distinct from both ssPPARß1A and the partial L92 cDNA, and was designated ssPPARß2A (corresponding to the L6 clone set). The other cDNA corresponded, with 100% nucleotide identity in the overlapping region, to the previously isolated partial L92 cDNA. This cDNA contained an open reading frame, which lacked a DNA-binding domain but possessed an intact A/B domain and LBD, and together with the gene in the L92 clone set was designated ssPPARß2B. The gene and cDNA sequences corresponding to the exons encoding the LBD of each of the presumed PPARß genes were aligned, together with exon-flanking regions (Fig. 2). The percentage identity matrices for these alignments showed that one of the cDNA sequences (ssPPARß1A) was identical to the gene present in the L1 clone set. The other full-length cDNA (ssPPARß2A) showed between 98 and 100% identity to clone set L6, whilst the atypical ssPPARß2B cDNA showed between 99 and 100% identity to the L92 clone set. Further attempts were made to isolate a cDNA (ssPPARß1B) corresponding to the L29 genomic sequence from gill, kidney, and muscle cDNA, but were unsuccessful. It should be noted that the materials for the construction of genomic and cDNA libraries were derived from different individuals; thus, the small differences observed between these cDNAs and genes are most likely the result of allelic variation within salmon populations. In addition, apparent from the identity matrices, the clone sets fall into two groups of two genes each, with about 80% identity between the members from different groups. Exon-flanking sequences from the genes were compared to determine whether the four genes were from distinct loci, or were allelic variants from two loci. From Fig. 2, it is apparent that, although there is some similarity in the exon-flanking regions between L29 and L1, and between L6 and L92 clone sets, there is a lower level of identity than might be expected of allelic variants. This indicates that there are at least four distinct PPARß genes in salmon.
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Comparison of the deduced amino acid sequences of the full-length ssPPARß1A and ssPPARß2A cDNAs clearly demonstrated that both salmon PPARs phylo-genetically clustered with PPARß subtypes from diverse vertebrates (Fig. 3). The salmon PPARs were most closely related to PPARs from other fish species. However, it is notable that, within the PPARß phylogeny, the two zebrafish PPARß isoforms do not resolve on the same branches as the salmon isoforms, and in any case their positions in the phylogeny are not well supported by bootstrap values. Most amino acid identity between the salmon isoforms and PPARß from other vertebrates was evident in the DNA- and ligand-binding regions, although there were also areas of cross-species identity in both the AB- and D-domains (Fig. 4). In both ssPPARß1A and ssPPARß2A, the amino acid residues that interact with fatty acid ligand and co-activator proteins are conserved (Nolte et al. 1998, Xu et al. 1999, Fyffe et al. 2006, Fig. 4).
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QPCR analysis of salmon PPARß expression across a range of tissues indicated that there were differences in relative expression levels (Fig. 5). ssPPARß1A was most highly expressed in liver and adipose, whilst ssPPARß2A was most highly expressed in gill and adipose. The levels of ssPPARß1A exceeded those of ssPPARß2A in liver. In gill, ssPPARß2A was the predominant isoform and both were expressed equally in adipose. The expression levels in other tissues were three- to fivefold lower than in liver, gill, and adipose, and there were no differences between the expression level of ssPPARß1A and ssPPARß2A.
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In cellular transfection assays (Fig. 6), there was a relatively small but significant activation of ssPPARß1A by palmitoleic acid. In contrast, there was no apparent effect of oleic, linolenic, arachidonic, eicosapentenoic, or docosahexaenoic acids. There was a much greater response to the mammalian PPARß-specific ligand GW501516 and bromopalmitate. However, L165041, another mammalian PPARß-selective ligand, was not an effective activator of salmon ssPPARß1A. Note that all compounds that resulted in the activation of ssPPARß1A also induced the basal activity of the reporter construct, suggesting the presence of endogenous ssPPARß1A. Indeed, QPCR indicated that ssPPARß1A was present (not shown) in the AS cell line although at lower levels per unit input RNA than any of the salmon tissues tested. This may indicate that fatty acids are effective activators of ssPPARß1A, since they all induced reporter gene activity significantly above that induced by the vehicle ethanol. Transfection of the ssPPARß2A significantly reduced the basal level of transcription from the reporter construct with all tested compounds (Fig. 6), suggesting repression of endogenous ssPPARß1A activity in the AS cell line. To test this, AS cells were transfected with both ssPPARßA1 and ssPPARß2A, and reporter gene activation measured after GW501516 treatment. The results confirmed (Fig. 7) that ssPPARß2A repressed both the basal and the GW501516-induced activity of ssPPARß1A, as well as the endogenous basal and induced activity.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The presence of four PPARß genes in salmonids is most probably a result of a relatively recent polyploidization event (60–90 million years), which is clearly evident in the evolution of salmonids (Allendorf & Thorgaard 1984). Moreover, more ancient polyploidization events have been proposed as a driving force for the evolution of the vertebrate lineage (Ohno 1970). One of these has been proposed to have occurred in the early evolution of ray-finned fishes (Taylor et al. 2003) and recent comparative syntenic analyses of zebrafish and pufferfish genomes (Woods et al. 2005) have supported this event and inferred subsequent lineage-specific duplications or losses to account for the differences in gene numbers between these species. The four PPARß genes in Atlantic salmon clearly group into two subfamilies most likely representing the polyploidization-dependent duplication of two PPARß subtypes from an ancestral diploid salmonid, these two genes arising from the more ancient ray-finned fish event. The phylogenetic analysis suggests that these two salmon subfamilies are not orthologous to the two PPARß subtypes in zebrafish, although it should be noted that the zebrafish sequences are not placed in the tree with high confidence and a definitive conclusion must await functional characterization of the zebrafish PPARß subtypes.
From an evolutionary perspective, a key question surrounding the process of polyploidizaton is how an individual with a polyploid genome would gain a selective advantage in a population and thence give rise to a new polyploid species. For such polyploidized individuals to reproduce successfully, they are required to undergo a process of diploidization concurrent with functional divergence of duplicated loci to obtain a selective advantage over their diploid relatives (Wolfe 2001). The genetic divergence of PPARß subtypes in salmon may be an example of the outcome of this diploidization process, and as such these genes would be expected to exhibit functional divergence. Indeed, our results indicate that ssPPARß1A or ssPPARß2A are differentially expressed and exhibit distinct activation characteristics. Levels of ssPPARß1A predominate in liver and ssPPARß2A predominate in gill and the differential expression of salmon PPARß isoforms has functional significance when the cellular transfection results are considered. It would appear that ssPPARß1A is similar in ligand-activation profile to PPARß from other species (Forman et al. 1997, Oliver et al. 2001, Leaver et al. 2005) being responsive to palmitoleic and oleic acids and to 2-bromopalmitate. Importantly, it is highly activated by the mammalian PPARß-selective ligand GW501516, but not activated by the PPAR-specific ligand WY146463. The response to GW501516 suggests that, as with PPARß in mammals, this compound is a ligand for ssPPARß1A. The identification of highly selective and potent ligands for fish PPARs is a necessary step in advancing understanding in this area and further studies are required to test whether GW501516 will be as selective and potent in salmon as it is in mammals. On the other hand, the lack of response of ssPPARß2A to fatty acids or PPARß-selective ligands is intriguing. Consideration of the LBD of ssPPARß2A suggests that this may be because there are critical differences between the sequence of this isoform and the sequences of mammalian or other characterized fish PPARß homologs. A number of amino acid residues are not conserved in the ssPPARß2A subtype (Fig. 4), which may change the characteristics of the LBD. However, none of these substitutions are at positions shown to be involved in either fatty acid ligand binding (Xu et al. 1999, Fyffe et al. 2006) or co-activator binding to human PPAR (Nolte et al. 1998), suggesting that ssPPARß2A may be capable of binding and being activated by as yet undiscovered ligands. It is possible that, if the two salmon subtypes have conserved functions and binding specificity, the true endogenous ligand for vertebrate PPARß may not be fatty acids, but might in future be identified as a compound which activates both ssPPARß1A and ssPPARß2A. Alternatively, the nonconserved substitutions or other characteristics of ssPPARß2A may prohibit ligand activation under any circumstances and its sole function may be to repress the activity of other PPARs. Mammalian PPARß has been shown to repress the activity of the other PPAR subtypes by competing for binding to PPREs (Shi et al. 2002). In this respect, the repressive ability of ssPPARß2A in both basal and GW501516-induced transcriptional activity is significant. The high levels of expression of ssPPARß2A in gill, in combination with its repressive activity, may have specific implications for the action of other PPAR subtypes in this tissue. As the fish gill is in close contact with the external environment, a single layer of epithelial cells separating the blood from the water, it is possible that in this tissue ssPPARß2A functions to repress the activity of other PPARs in order to prevent their un-programmed activation by exogenous compounds or contaminants. Thus, Atlantic salmon may have evolved novel PPARß-dependent processes. In this regard, it is important to note that other salmonids, such as rainbow trout and brown trout (Onchorhyncus mykiss and Salmo trutta), are also poly-ploid and would thus contain homologs of the four salmon PPARß genes. Previous studies (Batisto-Pinto et al. 2005, Lui et al. 2005) of tissue expression profiles and PPAR-agonist responses in these species have considered only a single PPARß subtype identified from partial cDNA sequences. In future, and in the light of these results from salmon, such studies should be conducted with the expectation of the presence of multiple PPAR subtypes with divergent function in trout and other salmonids.
In conclusion, these studies demonstrate the possibility for unexpected levels of variety in PPARß subtype and mechanism of action in Atlantic salmon, showing that further complexity in physiological control may result from functional divergence of duplicated nuclear receptor genes. Further studies are required to understand the role of these important regulators of lipid homeostasis in life cycle and evolutionary adaptation in salmonids and to determine common PPAR-dependent processes across all vertebrates.
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Acknowledgements |
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References |
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Received in final form 28 November 2006
Accepted 12 December 2006
Made available online as an Accepted Preprint 28 December 2006
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