doi: 10.1161/hq1201.100262
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Analysis of the Ileal Bile Acid Transporter Gene, SLC10A2, in Subjects With Familial Hypertriglyceridemia
From the Department of Internal Medicine (M.W.L., A.L.C., P.A.D.), Wake Forest University School of Medicine, Winston-Salem, NC; the Center for Metabolism and Endocrinology (B.A.), Department of Medicine, and Molecular Nutrition Unit (B.A.), Center for Nutrition and Toxicology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden; the Division of Metabolism, Endocrinology, and Nutrition (J.D.B.), Department of Medicine, University of Washington, Seattle; and GI Section (W.C.D.), Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis.
Correspondence to Dr Paul A. Dawson, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail pdawson{at}wfubmc.edu
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Abstract |
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Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na+/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5' flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2.
Key Words: bile acids • hypertriglyceridemia • genetics • complex disease
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Introduction |
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Familial hypertriglyceridemia (FHTG) is a heritable disorder of lipid metabolism characterized by elevated plasma VLDL triglyceride (VLDL-TG) levels. FHTG and familial combined hyperlipidemia (FCHL) were first described as autosomal dominant disorders with low penetrance before age 30 and distinct lipid profiles.1 In FCHL, plasma triglycerides and/or cholesterol may be elevated (lipoprotein phenotypes IIa, IIb, and IV), whereas FHTG is characterized by increased plasma VLDL-TG only (lipoprotein phenotype IV). FHTG is associated with higher production rates of VLDL-TG, larger triglyceride-rich particles, and an increased triglyceride-to-apoB ratio, whereas FCHL is associated with an increased production of VLDL apoB and smaller cholesterol-rich particles.2–4 VLDL-TG turnover studies showed that the metabolic defect in FHTG patients is triglyceride overproduction driving an increase in large triglyceride-enriched VLDLs.3,5
Candidate genes for FHTG have included those most directly involved in the production or catabolism of triglyceride-rich lipoproteins. In addition, the observation that alterations in bile acid metabolism affect plasma triglyceride levels suggests alternative candidate genes. Although the mechanism behind this relationship is unclear, a positive correlation between bile acid turnover and plasma VLDL-TG levels has been recognized for many years. Interruption of the enterohepatic circulation of bile acids with cholestyramine transiently increases plasma VLDL-TG levels.6–9 Similarly, patients that undergo ileal exclusion frequently develop mild hypertriglyceridemia (HTG) along with the expected bile acid malabsorption.10 This relationship is further supported by results from bile acid–feeding experiments. Patients administered chenodeoxycholic acid (CDCA) in gallstone dissolution studies exhibited decreased plasma triglyceride concentrations.11 The addition of CDCA to the diet has been shown to lower plasma VLDL triglyceride levels and bile acid synthesis rates.8,12,13 These studies illustrate that the flux of bile acids through the enterohepatic circulation is inversely related to plasma VLDL-TG levels. This relationship may be an important component of FHTG in a subset of patients. Patients with a type IV lipoprotein phenotype exhibit increased bile acid synthesis.14,15 Furthermore, the synthesis and fractional catabolic rates (FCRs) for bile acids are increased in many FHTG patients.16,17 These findings led to the hypothesis that intestinal bile acid malabsorption is the underlying defect in these patients.16–18 The first step in intestinal bile acid absorption is mediated by the ileal Na+/bile acid cotransporter (SLC10A2),19 which, as such, is a candidate gene for FHTG in these patients with abnormal bile acid metabolism. A mutation in SLC10A220 or a defect in its expression21 could explain the altered bile acid metabolism and, by an unknown mechanism, the concomitant increase in hepatic VLDL-TG production. With this rationale, we analyzed SLC10A2 in a group of HTG patients.
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Materials and General Methods
Genomic DNA was isolated from blood leukocytes by using a TurboGen Kit (Invitrogen Corp), or a Puregene Kit (Gentra Systems, Inc). [3H]Taurocholic acid (2.0 to 3.47 Ci/mmol) and [2,4-3H]cholate (27.5 Ci/mmol) were purchased from DuPont-New England Nuclear. Other tritiated bile acids (2 to 60 Ci/mmol) were obtained from Dr Alan Hofmann (University of California at San Diego) and were synthesized as described previously.22
Subjects
The present study was reviewed and approved by the Institutional Review Board of the Wake Forest University School of Medicine, and informed consent was obtained from all subjects at their individual institutions. Thirty (14 FHTG, 6 unclassified HTG, and 10 FCHL) male patients were included in the present study. FHTG patients were selected from families in which all affected members were lipoprotein phenotype type IV. FCHL patients were selected from well-characterized families in which at least 1 affected relative had only elevated plasma cholesterol (phenotype IIa). Secondary hyperlipoproteinemia and type III hyperlipoproteinemia were eliminated as possible confounding factors. The bile acid turnover analyses for the normolipidemic male subjects has been described previously.16,17,23 The normolipidemic control subjects for the genotyping analysis were selected from 195 healthy students (124 males and 71 females) from the Wake Forest University School of Medicine, and their lipid profiles have been described.20
Analysis of Bile Acid Turnover
Bile acid pool sizes, synthesis rates, and FCRs were determined as described previously15–18 by using the Lindstedt method24 or the 75Se homocholic acid taurine (75SeHCAT) test.25 For the Lindstedt method, subjects were given a standardized diet 7 days before the study. At the beginning of the study, subjects were given orally 5 µCi each of [14C]cholic acid ([14C]CA) and [14C]CDCA. The next morning and on 3 to 5 successive mornings, an aliquot of bile released from the gallbladder was collected to measure the radioactivity and mass of CA and CDCA. The specific activity decay curves were used to determine the FCR and the pool size of each primary bile acid. Synthesis rates were then calculated from those values. Data are presented individually or as mean±SEM. Statistical comparisons between groups were made by unpaired t test.
Genetic Analysis
Single-stranded conformation polymorphism (SSCP) analysis was performed as previously described20 by using the primers listed in online Figure IA and IB (which can be accessed at http://www.atvb.ahajournals.org). The polymerase chain reaction (PCR) samples were resolved on polyacrylamide gels containing 6%, 8%, and 10% acrylamide (ratio of acrylamide to N, N'-methylenebisacrylamide 50:1) and 8% acrylamide (ratio of acrylamide to N, N'-methylenebisacrylamide 29:1) to increase the assay sensitivity. The nucleotide changes responsible for the SSCP bands shifts were identified by PCR amplification and sequencing. Restriction endonuclease digestion with KpnI was used to detect the G insertion at codon 216 in exon 4 (646insG).
Site-Directed Mutagenesis and COS Cell Expression
A PCR-based strategy using Pfu polymerase was used for site-directed mutagenesis and to generate the Flag epitope–tagged constructs.20 The PCR products were subcloned into pCMV5, and the complete insert was sequenced to confirm the identity of the ileal Na+/bile acid cotransporter isoforms (V98I, V159I, A171S, and 646insG) and epitope-tagged cDNAs. For the expression studies, COS cells were transfected with the wild-type or mutant ileal Na+/bile acid cotransporter expression plasmids by the DEAE-dextran method26 or by use of FuGene 6 Transfection Reagent (Boehringer-Mannheim). The transfected cells were trypsinized, pooled, and replated at 2.2x105 cells per dish in 35-mm plates or at 7x104 cells per well in 24-well plates. After 48 hours, the cells were incubated at 37°C in Hanks’ balanced salt solution containing the indicated concentration of radiolabeled bile acid for the indicated times. The cell monolayers were washed and harvested to determine cell-associated protein and radioactivity.26
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Characterization of HTG Patients
The patients were classified as either FHTG/HTG or FCHL on the basis of their lipoprotein profiles and family history. The plasma triglyceride levels ranged from 1.2 to 16.1 mmol/L (upper limit of normal is
2.5 mmol/L). Total plasma cholesterol levels (range 3.9 to 8.4 mmol/L) were variable, with higher values generally found in FCHL subjects (Table 1). Information on FCRs for CA and CDCA (pools per day) and total bile acid synthesis (millimoles per day) are provided in Table 2. The patients are listed in order of decreasing FCRs for CA turnover. There was a wide range of FCR values, from 1.32 d-1 to 0.37 d-1 for CA and from 0.99 d-1 to 0.21 d-1 for CDCA. Total bile acid production ranged from 6.23 to 0.44 mmol/d. The total bile acid production and fractional turnover rates for CA and CDCA were significantly higher in the group of FHTG/HTG patients than in the group of FCHL patients or the control subjects (Table 2), in agreement with previous results.16–18
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Analysis of SLC10A2 in HTG Subjects
An SSCP strategy was used to determine whether SLC10A2 mutations are responsible for the bile acid malabsorption and HTG in these subjects. Analysis of the SLC10A2 coding region and intron/exon junctions revealed 4 coding region polymorphisms and 1 polymorphism near the exon 6 splice junction (Figure 1). The exon 1 and 2 SSCP band shifts were due to G-to-A transitions at codons 98 and 159, resulting in valine-to-isoleucine substitutions (V98I and V159I). The A171S polymorphism in exon 3 is common (carrier frequency 0.28) and has been reported previously.20 The intron 5 polymorphism (A-to-G transition) is located 20 bp upstream from exon 6 and does not fall within canonical splice site sequences. The exon 4 polymorphism, a 646insG, was found in only 1 individual (FHTG patient 5), who was heterozygous for this mutation. This nucleotide insertion at codon 216 causes a frameshift leading to a premature stop codon 30 amino acids downstream. To identify potential mutations affecting expression of the gene, the 5' flanking sequence of SLC10A2 was also screened by SSCP analysis. Four polymorphisms were identified, including a T-to-C transition at -768 (-768T/C), 2 nucleotide substitutions within a 4-bp region, CACT to TACC (-625TACC), an A-to-G transition at -458 (-458A/G), and a C-to-T transition at -225 (-225C/T). (The numbering is in reference to the initiator methionine, where A is position +1.) Relatively short pieces of DNA were amplified (153 to 305 bp, online Figure IA and IB), and 4 different gel conditions were used for the SSCP analysis to increase the assay sensitivity.20 However, the sensitivity of SSCP is not 100%, and mutations could have been missed by this analysis.
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Frequency and Distribution of SLC10A2 Polymorphisms
Figure 1 summarizes the results of the SSCP analysis. The uncommon polymorphisms in the FHTG/HTG groups were also found in the FCHL and control subjects. Similarly, the polymorphisms with the highest frequencies (-458A/G, A171S, and intron 5 -20G) were identified in all groups and did not appear to be enriched in any 1 category. The fact that there were 2 homozygotes in the normolipidemic control group (1 for V98I and 1 for intron 5 -20A/G) suggests that these 2 polymorphisms are functionally benign in vivo. The 646insG frame-shift mutation was found in only 1 FHTG subject (No. 5) and was the only coding region polymorphism exclusive to that group. The distribution of SLC10A2 polymorphisms among the FHTG/HTG and FCHL patients is shown in Table 2 for comparison with their bile acid kinetics. There was no apparent correlation between the SLC10A2 polymorphisms and the bile acid fractional turnover and synthesis in the FHTG/HTG or FCHL patients. In addition, there were no statistical differences between the various SLC10A2 isoform groups for the subjects’ bile acid kinetics (CA FCR, CDCA FCR, and total bile acid production) or plasma lipid levels (total plasma cholesterol, triglyceride levels, and HDL cholesterol); the probability value ranged from 0.08 to 0.94.
Analysis of Bile Acid Uptake Activity of Ileal Na+/Bile Acid Cotransporter Isoforms
To assess the effects of the V98I, V159I, and A171S substitutions on transporter function, the SLC10A2 isoforms were assayed for [3H]bile acid uptake activity in transiently transfected COS cells. As shown in Figure 2, the apparent Km for taurocholate uptake by the 3 isoforms was similar to the wild-type SLC10A2 protein. The activity differences between the isoforms reflect differences in their protein expression in the transfected cells. The transport activity per amount of transporter protein expressed is similar for the wild-type and V98I, V159I, and A171S isoforms (data not shown). The V98I, V159I, and A171S isoforms also transported all the major species of bile acids similar to the wild-type ileal Na+/bile acid cotransporter, indicating that the amino acid substitutions do not significantly alter substrate specificity (Figure 3).
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Analysis of the 646insG Mutation
The frame-shift mutation in exon 4 is predicted to encode a dysfunctional truncated protein. When transfected into COS cells, the 646insG mutation exhibited no [3H]taurocholate uptake activity above background (Figure 4A). The 646insG mutant transporter was epitope-tagged at the carboxyl terminus to determine whether the lack of transport activity was due to reduced expression of the truncated protein. In contrast to the wild-type transporter, no transport activity (Figure 4B) or transporter protein (online Figure II, which can be accessed at http://www.atvb.ahajournals.org) was detected in the 646insG-tag–transfected cells. The 646insG-tag protein was detected by using metabolic labeling and immunoprecipitation; however, the mass of the 646insG-tag protein was small compared with that of the wild-type transporter (online Figure II). These studies suggest that the mutant protein is synthesized but rapidly degraded by the quality control machinery in the cell.
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Although the 646insG mutation was found in only 1 of 20 subjects in the FHTG/HTG group, this mutation could still account for the FHTG phenotype. To address this question, the segregation of the G insertion with the FHTG phenotype was assessed by using restriction fragment length polymorphism analysis (online Figure III, which can be accessed at http://www.atvb.ahajournals.org). Patient 5 (pedigree subject I.2) and his daughter (pedigree subject II.1) carry the 646insG mutation. However, the 35-year-old daughter is not hypertriglyceridemic (her triglyceride level is between the 90th and 95th percentile for age and sex). This indicates that the 646insG mutation may not be the primary cause of this disorder. Alternatively, subject II.1 may be affected and will exhibit more HTG at an older age.
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Discussion |
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FHTG has been associated with abnormal intestinal absorption of bile acids.16–18 Although the cause-and-effect relationship between bile acid malabsorption and HTG remains to be established, a plausible explanation is that the reduced intestinal absorption of bile acids contributes directly to the hepatic overproduction of VLDL-TG. This hypothesis is supported by the observations that serum triglyceride levels rise after administration of bile acid–binding resins or ileal bypass and fall after the administration of CDCA to patients.6–13 In the present study, the human ileal Na+/bile acid cotransporter gene (SLC10A2) was examined to determine whether mutations are responsible for the intestinal bile acid malabsorption associated with FHTG. Analysis of SLC10A2 in a well-characterized group of FHTG/HTG patients with bile acid malabsorption revealed 9 sequence variations, including 3 coding region polymorphisms and a frame-shift mutation. The A171S substitution in exon 3 and intron 5 polymorphism (intron 5 -20A/G) were common in all groups, including the normolipidemic control subjects. Their high prevalence suggests that these polymorphisms are not important for the development of HTG. The conservative V98I and V159I substitutions were less common but were also found in the control subjects as well as in the HTG patients. One normolipidemic control subject was a V98I homozygote, suggesting that the polymorphism does not affect transport. In addition, the V98I, V159I, and A171S isoforms showed normal bile acid transport activity in a transfected COS cell assay. The only nonfunctional mutation was the 646insG in exon 4, which was found in 1 FHTG patient. This mutant protein exhibited no bile acid–uptake activity in vitro, most likely reflecting rapid degradation of the truncated transporter. Although this mutation could account for the bile acid malabsorption in patient 5, analysis of the segregation of this mutation and the FHTG phenotype was inconclusive. It is also noteworthy that patient 5 presented with no gastrointestinal complaints (such as the diarrhea or steatorrhea) despite being heterozygous for this mutation and exhibiting relatively high turnover rates for both primary bile acids.
The 5' flanking sequence was also screened because mutations in this region may affect gene expression. Four polymorphisms were identified; however, none of the polymorphisms were located in the predicted transcription factor–binding sites, including the hepatocyte nuclear factor-1
–binding site, which was recently shown to be important for SLC10A2 expression.27 The -458A/G polymorphism is common in FHTG, FCHL, and control subjects. The -625TACC polymorphism occurred with low frequency and in all groups. There were 2 polymorphisms (-768T/C and -225C/T) that were identified in only 1 FHTG/HTG individual each. Comparison of the 5' flanking sequence for human, rat, and mouse SLC10A2 suggests that both polymorphisms have little effect on function, inasmuch as the -768C and -225T are the wild-type sequence in the rat and mouse genes.
In summary, 12 of 20 FHTG/HTG patients carried at least 1 SLC10A2 polymorphism, and 9 of 20 patients had multiple polymorphisms. However, the fact that these polymorphisms were also observed in FCHL patients and control subjects diminishes the significance of these findings. Moreover, there was no apparent correlation between any of the SLC10A2 polymorphisms and the bile acid production or turnover in these patients. These results indicate that the mutations in SLC10A2 do not account for the decreased intestinal bile acid absorption in these FHTG/HTG patients or for the decreased SLC10A2 mRNA and protein expression recently demonstrated in HTG.21 The reason for this decreased SLC10A2 expression in HTG is unknown. However, it will be important to identify the transcription factors important for SLC10A2 expression, because defects in those factors may contribute directly or indirectly to the intestinal bile acid malabsorption and HTG phenotype.
Regardless of the putative defect in these FHTG patients, the inverse relationship between bile acid flux through the enterohepatic circulation and plasma VLDL-TG concentrations indicates that cross talk exists between these pathways. Stimulation of VLDL-TG synthesis by interruption of the bile acid enterohepatic circulation may or may not lead to HTG, depending on the capacity to metabolize VLDL. The FHTG phenotype could be explained by a defect in a single factor that normally influences intestinal bile acid absorption, hepatic bile acid synthesis, and hepatic triglyceride metabolism. A candidate for such a factor is the bile acid–activated nuclear orphan receptor (farnesoid X-activated receptor [FXR]) that regulates bile acid synthesis and transport.28–30 FXR has been shown to repress bile acid biosynthesis by inducing the expression of short heterodimer partner-1, which functions to inhibit liver receptor homologue-1, a competence factor essential for cholesterol 7-hydroxylase gene transcription.28,29 Bile acids may act similarly through FXR to repress hepatic VLDL-TG production. Several recent studies indirectly support this model. Administration to rats of a non–bile acid FXR agonist, GW4064, resulted in a dose-dependent decrease in serum triglyceride levels similar to previous bile acid–feeding studies in rats and humans.31 Conversely, disruption of bile acid signaling in the liver by targeted disruption of FXR in mice resulted in increased hepatic triglyceride contents and elevated serum triglyceride levels,32 analogous to bile acid malabsorption states.
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Acknowledgments |
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This work was supported by National Institutes of Health grants DK-47987 and HL-49373 (P.A.D.) and HL-30086 (J.D.B.), by the Swedish Research Council (No. 03X-7137), and by the Swedish Heart-Lung Foundation (B.A.). M.W. Love was supported by a National Institutes of Health Cardiovascular Pathology Institutional National Service Training Award (No. HL-07115). P.A. Dawson is an Established Investigator of the American Heart Association.
Received July 31, 2001; accepted September 26, 2001.
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