Identification of a Novel Gene Family Encoding Human Liver-specific Organic Anion Transporter LST-1*

Takaaki AbeDagger §, Masayuki KakyoDagger §parallel , Taro Tokui§**, Rie Nakagomi**, Toshiyuki NishioDagger Dagger , Daisuke Nakai**, Hideki NomuraDagger , Michiaki Unnoparallel , Masanori Suzukiparallel , Takeshi Naitohparallel , Seiki Matsunoparallel , and Hiromu YawoDagger

From the Dagger  Department of Neurophysiology, parallel  1st Department of Surgery, Dagger Dagger  Department of Pediatrics, Tohoku University School of Medicine, Sendai, 980-8575 and ** Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, 140-8710, Japan

    ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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We have isolated a novel liver-specific organic anion transporter, LST-1, that is expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene family located between the organic anion transporter family and prostaglandin transporter. LST-1 transports taurocholate (Km = 13.6 µM) in a sodium-independent manner. LST-1 also shows broad substrate specificity. It transports conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta -glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, leukotriene E4), and thyroid hormones (thyroxine, Km = 3.0 µM and triiodothyronine, Km = 2.7 µM), reflecting hepatic multispecificity.

LST-1 is probably the most important transporter in human liver for clearance of bile acids and organic anions because hepatic levels of another organic anion transporter, OATP, is very low. This is also the first report of the human molecule that transports thyroid hormones.

    INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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One of the major function of the liver is the removal of various endogenous and exogenous compounds from the circulation (1, 2). This clearance process involves basolateral membrane transport systems that mediate the hepatocellular uptake of bile acids, organic anions, and organic cations (3, 4). One well studied class of substrates are the bile acids. The uptake of taurocholate is mainly mediated by the Na+/taurocholate cotransporting polypeptide (ntcp) in a Na+-dependent manner (5). The uptake of other bile acids (e.g. cholate) occurs predominantly via a Na+-independent mechanism (2, 4). Some amount of taurocholate is also transported by the Na+-independent mechanism. This Na+-independent carrier system further shows a broad substrate specificity transporting conjugated steroids, cardiac glycosides, and other xenobiotics (4).

Initially, the organic anion transporter (oatp)1 family (oatp1, oatp2, oatp3) was considered to represent the Na+-independent transporting mechanisms in the liver (6-8). Subsequently, a human cDNA, termed OATP, was isolated (9). However, significant differences were found between human OATP and rat oatp family. First, although the substrate specificities were qualitatively similar, significant differences were found between human OATP- and rat oatp family-mediated initial uptake rates and apparent Km values (10, 11). Second, Northern blot analysis of the human OATP showed considerably high expression in the brain, a pattern that is different from any of the oatp family members. These findings strongly suggest the existence of a different group of organic anion transporters in human liver.

Here we report the isolation of a novel human organic anion transporter, termed LST-1, which is expressed exclusively in the liver. When expressed in Xenopus oocytes, many of the functional characteristics of LST-1 were identical to the multispecific transporting mechanisms of human liver. These results suggest that LST-1 is the predominant clearance mechanism of several endogenous and exogenous substrates in human liver.

    MATERIALS AND METHODS
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Isolation of the Human LST-1 cDNA-- The GenBankTM data base dbEST was searched with all known mammalian oatp family and the prostaglandin (PG) transporters (6-9, 12-14) using the TBLASTN algorithm. As a result, three independent clones that have weak to moderate similarity to both the oatp family and the PG transporter were identified (GenBankTM accession numbers H62893, T73863, and R29414). Polymerase chain reaction primers were designed from each EST sequence, and the amplified products were subcloned into pBluescript. A human liver cDNA library was constructed by the lambda ZAPII vector (Stratagene) (15). 5 × 105 independent clones were screened with each EST clone under high stringency. As a result, the signals hybridized with each EST clone were identical with each other. In a series of screenings, 52 hybridization-positive clones were isolated, and the clone that had the largest insert (pH1) was chosen for further analysis. The sequences were determined using ABI PrismTM 377 DNA sequencer (Perkin-Elmer).

Homology Analysis-- Multiple sequence alignments of amino acid sequences and phylogenetic tree construction were carried out using Clustal W (16). The phylogenetic trees were described by TreeView (17).

Northern Blot Analysis-- Multiple tissue NorthernTM blots containing 2 µg of human, rat, and mouse mRNAs were purchased (CLONTECH). Filters were hybridized with the 32P-labeled fragment of the 3'-untranslated region of pH1 (EcoRI-EcoRI, 838 base pairs) for human and with full-length cDNA of pH1 for rat and mouse Northern blot analyses. For human OATP analysis, the 3'-untranslated region (HindIII-EcoRI, 830 base pairs) was used to discriminate the cross-hybridization. In human Northern blot analyses, filters were hybridized in a buffer containing 50% formamide, 5 × SSC (1× SSC = 0.15 M NaCl and 0.015 M sodium citrate), 5 × Denhardt's solution, and 1% SDS at 42 °C overnight, washed in 0.2× SSC, 1% SDS at 65 °C for 1 h, and exposed to a film at -80 °C for 3 h (human LST-1) or 3 days (human OATP). For rat and mouse Northern blot analyses, filters were hybridized in a buffer containing 25% formamide, 5× SSC, 5× Denhardt's solution, and 1% SDS at 42 °C overnight, washed in 2× SSC, 1% SDS at 55 °C for 1 h, and exposed to a film at -80 °C for overnight (mouse) or 4 days (rat). The human beta -actin probe was used to monitor the quality of the mRNAs.

Expression of LST-1 in Xenopus Oocytes-- The isolated clone pH1 was linearized, and the capped cRNA was transcribed in vitro with T7 RNA polymerase (Stratagene). Xenopus laevis oocytes were prepared as described previously (7). Briefly, defolliculated oocytes were microinjected with 10 ng of transcribed cRNA and were cultured for 72 h in a modified Barth's medium (88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO3, 0.3 mM Ca(NO3)2, 0.41 mM CaCl2, 0.82 mM MgSO4, 15 mM Hepes, pH 7.6) at 18 °C. Uptake of radiolabeled chemicals was measured in a medium containing 100 mM NaCl, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM Hepes, pH 7.5. Oocytes were incubated in 100 µl of the same medium containing radiolabeled substrate at room temperature. Uptake was terminated by the addition of 3 ml of ice-cold uptake buffer, and the oocytes were washed 3 times. The water-injected oocytes were used as controls. The statistical significance was tested by unpaired t test.

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Isolation and Structural Analysis of LST-1-- The isolated cDNA encoding human LST-1 consisted of 691 amino acids (Mr 78.912), and the hydrophobicity analysis (18) suggested the presence of 12 transmembrane domains (Fig. 1a). There are seven putative N-glycosylation sites in the predicted extracellular loops, one potential phosphorylation site for cAMP-dependent protein kinase, and one potential phosphorylation site for protein kinase C in the third cytosolic hydrophilic loop (19, 20). The sequence homology analysis revealed a moderate sequence similarity to both the oatp family and the PG transporter, which is moderately related to the oatp family. The overall amino acid sequence identities were 42.2% for human OATP (9), 42.9% for rat oatp1 (6), 43.6% for rat oatp2 (7, 8), 43.9% for rat oatp3(7), 42.0% for rat OAT-K1 (12), 33.0% for rat PG transporter (13), and 34.9% for human PG transporter (14). The phylogenetic tree analysis by using the neighbor-joining and the maximum-likelihood methods showed that LST-1 is positioned between the oatp family and the PG transporter (Fig. 1b).


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Fig. 1.   a, alignment of the deduced amino acid sequence of LST-1 (GenBankTM accession number AF060500), human OATP, and human PG transporter (PGT). The sequences are aligned with single-letter notation by inserting gaps (-) to achieve the maximum homology. The 12 putative transmembrane segments (I to XII) were assigned on the basis of hydrophobicity analysis. Sequence motifs for potential N-glycosylation sites (triangles) and possible phosphorylation sites (asterisks) are indicated. b, phylogenetic relationship between LST-1, the oatp family, and PG transporter. The phylogenetic tree was constructed using CLUSTAL W and TreeView (http://taxonomy.zoology.gla.ac.uk/rod/treeview.html) using ungapped regions and distance correction. Branch lengths are drawn to scale.

Northern Blot Analyses-- Northern blot analysis of the LST-1 showed two bands (one major band at 3.0 kilonucleotides and one minor band at 4.8 kilonucleotides) exclusively in the liver (Fig. 2a). No significant expression was detectable in any of the other tissues examined. The rat and mouse Northern blot analyses with the human LST-1 probe also detected a single band only in the liver (Fig. 2, b and c), suggesting that LST-1 and the rat and mouse homologues are liver-specific.


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Fig. 2.   Northern blot analysis of the human LST-1 mRNA. a, human Multiple Tissue NorthernTM blots (2 µg of Poly(A)+ RNAs) were hybridized with the 3'-noncoding region (the 838 base pairs EcoRI-EcoRI fragment) of the human LST-1. Rat (b) and mouse (c) Multiple Tissue NorthernTM blots (CLONTECH) were hybridized with the full length of the human LST-1 under low stringency. d, human Multiple Tissue NorthernTM blots were hybridized with the HindIII-EcoRI (830 base pairs) fragment of human OATP, which has less than 45% homology with both human LST-1 and human PG transporter. In a and d, hybridization of each blot with beta -actin has been further performed to ensure the quality of the mRNA. The size marker (kilonucleotides) used was the RNA ladder.

Because Kullak-Ublick et al. (9) reported the presence of human OATP transcript in the liver, Northern blot analysis for the human OATP was further performed. The signals were detected only in the brain at 8.0 and 2.8 kilonucleotides (Fig. 2d), indicating that the expression of OATP is negligible in human liver.

To confirm this, we re-screened the human liver cDNA library filters that were used for isolating LST-1 with the human OATP probe. All the signals detected with the human OATP probe were completely overlapped with the positive signals detected by the LST-1 probe. To further characterize the OATP-positive signals, we designed the polymerase chain reaction primers at the 3'-noncoding region of human OATP, and amplification was performed. Among 52 LST-1-positive signals, no polymerase chain reaction positive band was detected. Because the human liver library used was not amplified, each positive signal was independent and tentatively represented the population of the original human liver mRNA. These data revealed that LST-1 is exclusively expressed in the human, rat, and mouse liver, whereas OATP is expressed in the human brain.

Pharmacological Characterizations-- Based on the structural similarities observed between the oatp family and the PG transporter, we assumed that LST-1 can transport both organic anions (i.e. taurocholate and conjugated steroids) and eicosanoids. In the oocytes injected with LST-1 cRNA, [3H]taurocholate was transported according to the saturation kinetics with an apparent Km of 13.6 ± 5.6 µM (Fig. 3). This LST-1-mediated [3H]taurocholate uptake was not inhibited by replacing the extracellular Na+ with choline (p > 0.1), reflecting the Na+-independent fraction in human liver. The LST-1-expressing oocytes also significantly transported conjugated steroids dehydroepiandrosterone sulfate, estradiol-17beta -glucuronide, and estrone-3-sulfate (Table I). In contrast, unconjugated steroids such as aldosterone, estradiol, and testosterone were not transported.


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Fig. 3.   Transport of taurocholate in LST-1-expressing oocytes. The transport rates of [3H]taurocholate for the LST-1 cRNA-injected oocytes were measured (20 min). From all uptake values, nonspecific uptake into water-injected oocytes was subtracted. A representative of three experiments is shown. The values indicated are means ±S.E. of 5~9 oocyte determinations.

                              
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Table I
Uptake of 3H-labeled various compounds by LST-1-expressing oocytes
The uptake experiments were performed at the concentration indicated for 60 min. Values are mean ±S.E. of 8~15 oocytes determinations. The significance between water-injected and LST-1-cRNA-injected oocytes was determined by unpaired t test.

Moreover, the oocytes injected with LST-1 cRNA transported PG E2, thromboxane B2, leukotriene C4, and leukotriene E4 (Table I). On the other hand, no arachidonic acid uptake was detected.

We have previously reported that oatp2 and oatp3 transport both thyroxine (T4) and triiodothyronine (T3) (7). The LST-1 cRNA-injected oocytes significantly transported [125I]T4 and [125I]T3 in a saturable manner. The apparent Km values for [125I]T4 and [125I]T3 were 3.0 ± 1.3 µM and 2.7 ± 1.1 µM, respectively (Fig. 4, a and b). These LST-1-mediated T4 and T3 uptakes were also Na+-independent (data not shown). Thus, these data demonstrated that LST-1 encodes a human liver-specific multifunctional transporter that transports taurocholate, conjugated steroids, eicosanoids, and thyroid hormones in accordance with the structural characteristics.


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Fig. 4.   Transport of thyroid hormones in LST-1-expressing oocytes. The transport rates of T4 (a) and T3 (b) for the LST-1 cRNA-injected oocytes were measured (20 min). A representative of three experiments is shown. The values indicated are means ±S.E. of 8~15 oocyte determinations.


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ABSTRACT
INTRODUCTION
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The present study describes the isolation of a new gene family encoding human liver-specific organic anion transporter, LST-1. LST-1 appears to be an essential transporter in human liver for the following reasons.

LST-1 Is a Member of a Novel Super Gene Family Expressed in the Liver-- A comparison of the LST-1 amino acid sequence to that of human OATP and PG transporter revealed that, although the transmembrane regions and its surrounded area are moderately conserved, the N- and C-terminal cytoplasmic regions are completely different (Fig. 1a). The phylogenetic tree analysis also revealed that LST-1 is branched between human OATP and PG transporter (Fig. 1b). Therefore, we propose LST-1 as a novel gene family.

Northern blot analysis showed that the LST-1 mRNA is exclusively expressed in human liver (Fig. 2a). The rat and mouse Northern blot analyses with LST-1 as a probe also detected a single band only in the liver (Fig. 2, b and c). In rat, four oatp family members have been reported (6-8, 12). Among these, oatp1, oatp2, and oatp3 are expressed in the liver, but their expressions are not liver-specific. The PG transporter is also widely distributed (13, 14). These data strongly suggest that human LST-1 is not the counterpart of the oatp family or the PG transporter, but it belongs to another new super gene family exclusively expressed in the liver.

Human Organic Anion Transporters Distribute in a Organ-specific Manner-- Northern blot analysis using the 3'-noncoding region of human OATP detected signals only in the brain (Fig. 2d). Although a previous study showed a rather broad distribution (9), this discrepancy is probably because of the cross-hybridization of the less-specific probe. Thus, in human, OATP appears not to be the principal organic anion transporter in the liver but to be the main transporter in the brain. These data further suggest that, in human, the organic anion transporters are assumed to be expressed in an organ-specific manner.

Pharmacological Properties Are Similar to Human Liver-- Functional analysis for LST-1 revealed that LST-1 transported taurocholate (Km, 13.6 µM) in a Na+-independent manner (Fig. 3). This value is approximately two to four times lower than those of the oatp family and human OATP (7-9, 21), whereas it is comparable with that of the human hepatocyte when extracellular Na+ was removed (22). These data suggest that LST-1 is the molecule representing the Na+-independent bile acid uptake in human liver. Furthermore, in the liver, interspecies differences of taurocholate uptake between rat and human liver have been reported (4, 22). These functional differences can be explained by the difference in the major organic anion transporter molecule in rat and human liver: LST-1 in human and oatp family members in rat.

The oatp family transports bile acids but does not transport eicosanoids (PG E2, PG F2alpha , and thromboxane B2) (21, 23). On the other hand, the PG transporter transports PG E1, PG E2, PG F2alpha , and thromboxane B2 but does not transport taurocholate (13, 14, 24). Our study shows that the substrate specificities of the LST-1 are intermediate; it transports taurocholate, conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta -glucuronide, and estrone-3-sulfate) and eicosanoids (PG E2, thromboxane B2, leukotriene C4, and leukotriene E4) (Figs. 3 and 4; Table I). It is speculated that this wide substrate specificity would be explained by the structure of the LST-1, because LST-1 is structurally located intermediately between the oatp family and the PG transporter.

Our previous data revealed that both rat oatp2 and oatp3 transport thyroid hormones (7). LST-1 cRNA-injected oocytes transported T4 and T3 (Fig. 4, a and b). In human liver, carrier-mediated transport of thyroid hormone has been predicted (25, 26). Thus, this is the first report identifying a human molecule that transports thyroid hormone, and these findings should be a tool for understanding the delivery of thyroid hormone to tissue in human (27).

Taken together, it is concluded that in human, LST-1 should be the essential molecule for transporting bile acids and organic anions in the liver, reflecting the multispecificity of the Na+-independent clearance mechanism in vivo.

So far, in human, the Na+-independent fraction of bile acid and organic anion transport in the liver have been discussed by using human OATP as a responsible molecule. However, the present study reveals that LST-1 may actually be the essential molecule in human liver, and the hepatic expression of human OATP is negligible. Further studies of LST-1 should provide new insight into bile acid formation and greater understanding of the pathogenesis of the diseases such as cholestasis (28), hyperbilirubinemia (29), and thyroid hormone resistance (Refetoff's syndrome) (30). Our findings may also be a new guide to develop the liver-specific drug delivery system and liver-specific chemotherapy (31).

    ACKNOWLEDGEMENT

We thank to Dr. Kazuo Nunoki for discussions.

    FOOTNOTES

* This work was supported in part by research grants from the Ministry of Education, Science, and Culture of Japan, the Yamanouchi Foundation for Research on Metabolic Disorders, the Nishimiya Foundation, the Tokyo Biochemical Research Foundation, the Japan Research Foundation for Clinical Pharmacology, and the Inamori Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF060500.

§ These authors contributed equally to this study.

To whom correspondence should be addressed: Dept. of Neurophysiology, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, 980-8575, Japan. Tel: +81-22-717-8153; Fax: +81-22-717-8154; E-mail: takaabe{at}mail.cc.tohoku.ac.jp.

    ABBREVIATIONS

The abbreviations used are: ntcp, Na+/taurocholate cotransporting polypeptide; oatp, organic anion-transporting polypeptide; PG, prostaglandin; T4, thyroxine; T3, 3,5,3'- triiodo-L-thyronine.

    REFERENCES
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REFERENCES
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