Children's Foundation Research Center of Memphis at Le Bonheur Children's Medical Center, University of Tennessee Health Science Center, Memphis, Tennessee 38103
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ABSTRACT |
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Dietary lipid
acutely upregulates apolipoprotein (apo) A-IV expression by sevenfold
at the pretranslational level in neonatal swine jejunum. To determine
the mechanism of this regulation, two-day-old female swine received
intraduodenal infusions of low- and high-triacylglycerol (TG)
isocaloric diets for 24 h. Nuclear runoff assay confirmed apo A-IV
gene transcriptional regulation by the high-TG diet. Footprinting
analysis using the swine apo A-IV proximal promoter sequence (+14 to
246 bp) demonstrated three regions protected by the low-TG extracts.
Of these three motifs, only ACCTTC showed 100% homology to the human
sequence and was further studied. EMSA was performed using probes
containing wild-type (WT) and mutant (M) motifs. A shift was noted with
the low-TG nuclear extracts with the WT probe but not with the M probe. Excess unlabeled free WT probe competed out the shift, whereas the M
probe did not. No significant shift occurred with either probe using
high-TG extracts. These results suggest that a repressor protein binds
to the ACCTTC motif and becomes unbound during lipid absorption,
allowing transcriptional activation of the apo A-IV gene in newborn
swine small intestine.
DNAse I DNA protection assay; electrophoretic mobility shift assay; gene transcription; nuclear runoff assay; small intestine
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INTRODUCTION |
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LIPID IS AN ESPECIALLY IMPORTANT nutrient in the neonatal period and is a major component of breast milk. Important events in the absorption of dietary lipid are uptake and reesterification of the products of lipid digestion, packaging of these complex lipids with apolipoproteins into nascent chylomicrons in the endoplasmic reticulum, trafficking of the prechylomicron to the Golgi apparatus, and finally the basolateral secretion of the chylomicron for entry into the systemic circulation (28). Regulation of small intestinal apolipoprotein expression during this process is especially important, because these lipid-binding peptides play important roles in the assembly, secretion, and peripheral metabolism of lipoprotein particles.
Apolipoprotein (apo) A-IV is an abundant apolipoprotein synthesized by both the liver and small intestine in rodents and by intestine only in humans and swine (4, 7, 13-15, 19). Apo A-IV is a component of nascent intestinal lipoproteins, including chylomicrons and HDL, and becomes dissociated from chylomicrons soon after secretion. Several studies have suggested roles for apo A-IV in the activation of lecithin-cholesterol acyltransferase (10, 33), in reverse cholesterol transport by promoting cellular cholesterol efflux (32), as a ligand for HDL binding to hepatocytes (12), and in activation of lipoprotein lipase by the augmentation of apo C-II transfer from HDL (18). Recent work suggests a role for apo A-IV as a postprandial satiety factor and as an inhibitor of gastric acid secretion in the adult rat, with these effects mediated at the level of the central nervous system (16, 17, 29). Apo A-IV also appears to function as an endogenous lipoprotein antioxidant (30). We (27) recently published evidence that apo A-IV may enhance lipid transport in the newborn enterocyte.
Genes for apo A-IV, C-III, and A-I form a cluster on chromosome 11 in the human (24). The apo C-III gene is located downstream from the apo A-I gene and upstream from the apo A-IV gene. The apo C-III gene is transcribed in the opposite direction to that of the apo A-I and A-IV genes. Tissue-specific and basal regulation of apo A-I, C-III, and A-IV gene transcription has been the focus of extensive study, and relevant cis- and trans-acting factors have been identified (5, 25).
We have previously demonstrated that dietary lipid acutely (24 h) upregulates apo A-IV expression by sevenfold at the pretranslational level in newborn swine proximal small intestine (7, 8). By 2-3 wk of age, the magnitude of this upregulation is reduced to about twofold, which is comparable with that observed in the adult rat (2, 7). The present studies were undertaken to determine the molecular mechanism of this enhanced regulation of apo A-IV expression in newborn intestine by dietary lipid.
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MATERIALS AND METHODS |
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Animals.
To study the short-term (24 h) physiological regulation of apo A-IV
expression by dietary lipid in newborn swine small intestine, 2-day-old
female swine (Tyson Farms, Plummerville, AR) were surgically fitted
with duodenal catheters exiting through dorsal swivel tethers as
previously described (6). Animals were allowed to recover for 24 h while receiving a glucose-saline (5% glucose in 45 mM NaCl and 20 mM KCl) duodenal infusion at 100 ml · kg1 · 24 h
1, followed by the infusion of either dilute Vivonex
(Norwich Eaton Pharmaceuticals, Norwich, NY), a low-fat elemental
formula, or Intralipid (Cutter, Berkeley, CA), a lipid emulsion
containing primarily 18-carbon unsaturated fatty acids. Infusions were
isocaloric and at a rate of 50 kcal · kg
1 · 24 h
1. At the end of the 24-h infusion, animals were
anesthetized and the abdominal cavity was quickly opened for harvest of
the intestine. Sections of jejunum were taken 5 cm distal to the
ligament of Treitz for preparation of nuclei and nuclear extracts, as
well as total RNA. Animals were then euthanized by intracardiac
pentobarbital overdose. All procedures were approved by the University
of Tennessee Health Science Center Animal Care and Use Committee.
Materials. All radioisotopes were purchased from DuPont New England Nuclear (Boston, MA). PMSF and DTT were purchased from Sigma (St. Louis, MO). Unless otherwise specified, all other chemicals were molecular biology grade and were purchased from Sigma.
Cloning and sequencing of the swine apo A-IV proximal promoter. The swine apo A-IV gene proximal promoter was PCR-amplified from swine genomic DNA using primers 5'-TGTCA/TGCTTCCACGTA/TGTCT-3' and 5'-ACNGCCTTCAGGAACATCCTG-3' derived from the corresponding human sequence. A 261-bp PCR product was amplified and cloned into the TOPO TA cloning vector (Invitrogen, Carlsbad, CA) for automated sequencing.
Isolation of RNA. Swine jejunal enterocytes were scraped and dissolved in TRI reagent (Molecular Research Center, Cincinnati, OH) at a concentration of 50-70 mg/ml, followed by extraction of total RNA.
RT-PCR.
Aliquots of RNA (2-10 µg) were treated with 0.5 units of
DNAse RQ1 (Promega, Madison, WI) at 37°C for 60 min in 50 µl of the following (in mM): 40 Tris · HCl, pH
7.5, 6 MgCl2, 10 NaCl, 10 DTT, and 20 units RNAse inhibitor
(RNAsin; Promega). The RNA was then sequentially extracted with
phenol-chloroform and chloroform, precipitated with ethanol, washed
once (with 70% ethanol), and resuspended in 20-40 µl
H2O. For reverse transcription, 5-µg total RNA was used.
Reverse transcription was performed at 42°C for 60 min in a final
volume of 50 µl in buffer containing 10 mM
Tris · HCl, pH 8.3, 90 mM KCl, 1 mM
MnCl2, 200 µM of each dNTP, 0.5 µg
oligo(dT)15 as primer, and 10 units Moloney murine leukemia virus (MMLV) reverse transcriptase (GIBCO-BRL, Grand Island,
NY). After reverse transcription, the single-strand cDNA was amplified using the Qiagen Taq PCR core kit (Qiagen, Santa Clarita,
CA) with 1 µl cDNA and 100 pmol of each specific primer in a total volume of 50 µl. After incubation for 60 s at 94°C, PCR was
performed for 23 cycles for -actin and 25 cycles for apo A-IV in a
thermal cycler (PerkinElmer, Boston, MA) as follows: 10 s at
94°C, 10 s at 62°C for apo A-IV and 61°C for
-actin, and
60 s at 72°C ending with 5 min at 72°C. For each RNA sample a
negative control was run to check for DNA contamination using AmpliTaq
(PerkinElmer), leaving the sample on ice during reverse transcription.
Additionally, each reaction contained a tube with all of the above
buffers and enzymes but without RNA to exclude PCR product
contamination. The optimal number of PCR cycles for each set of primers
was established by constructing curves of the number of cycles vs. PCR
product band density in agarose gels. Cycle numbers were selected in
the linear portion of the curves. After RT-PCR, 2/5 of the reaction products were subjected to 1.5% agarose gel electrophoresis. Expected product sizes were confirmed as follows:
-actin, 410 bp and apo A-IV, 492 bp. Agarose gels containing PCR products were stained with
ethidium bromide and imaged on the Gel-Doc 2000 (Bio-Rad, Hercules, CA).
Oligonucleotides for PCR.
Oligonucleotides were as follows: -actin forward,
5'-TGGCATTGTCATGGACTCTG-3' (sense, nt 81-100) and reverse,
5'-CGCACTTCATGATCGAGTTG-3' (antisense, nt 471-490); swine
apo A-IV forward, 5'-GAACGCCTGACCAAGGACTG-3' (sense, nt 265-284)
and reverse, 5'-CAGCTCCTCTGCCTGCTTCT-3' (antisense, nt 737-756).
Isolation of nuclei and nuclear runoff assay.
Nuclear runoff analysis of apo A-IV and -actin gene transcription
were performed as described (20). Two-day-old newborn swine received 24-h intraduodenal isocaloric infusions of either low-triacylglycerol (low-TG) or high-TG diets, followed by harvest of
the proximal half of the small intestine from which nuclei were
prepared. Nuclear runoff assay was performed by incubating 5 × 107 nuclei per preparation with [
-32P]UTP
plus unlabeled nucleotides. Newly transcribed RNA was extracted from
the reaction mixture, and 3 × 106 dpm from each group
was hybridized with nitrocellulose filters with slots containing 5 µg
each of bound linearized plasmids containing swine apo A-IV and
-actin cDNA inserts. Filters were washed at high stringency and
subjected to autoradiography followed by digital densitometry.
Isolation of nuclear extracts. Nuclear extracts were prepared from newborn swine enterocytes and hepatocytes as described (1). Briefly, enterocytes were scraped from newborn piglet proximal jejunum and washed with cold PBS and cold hypotonic buffer (in mM: 10 HEPES, pH 7.9, 1.5 MgCl2, 10 KCl, 0.2 PMSF, and 0.5 DTT). Hepatocytes were similarly isolated and washed. The pellet was resuspended in 3 volumes of hypotonic buffer and incubated on ice for 5 min. After homogenization, the pellet containing the nuclei was collected by centrifugation for 15 min at 3,300 g. Nuclear extract was prepared by incubation with low (0.02 M KCl) and high (1.2 M KCl) salt buffer. The extract was dialyzed against 50 volumes of dialysis buffer (in mM: 20 HEPES, pH 7.9, 100 KCl, 0.2 EDTA, 0.2 PMSF, and 0.5 DTT and 20% glycerol) at 4°C.
DNAse I DNA protection assay.
DNAse I DNA protection assays were conducted using the Promega Core
Footprinting System (Madison, WI). Each assay used 2.5 and 5 µg of
nuclear extract protein, 15,000 counts/min of radiolabeled DNA
probe, and binding buffer in a total volume of 50 µl. After incubation for 10 min at room temperature, 0.05 µg of RQ1 was added
to the mix, followed by incubation at 37°C for 2 min. Digested DNA
probes were purified and loaded onto a 6% polyacrylamide gel. Gels
were electrophoresed at 1,500 V/60 watts in 1× Tris-borate-EDTA (TBE)
buffer. Gels were then dried and subjected to autoradiography at 80°C overnight. Nuclear extract from HeLa cells was provided in
the Promega kit.
EMSA.
EMSAs were performed using the Stratagene GelShift Assay Kit
(Stratagene, La Jolla, CA) according to the manufacturer's protocol. Assays used 2.5 and 5 µg of nuclear extracts and 15,000 counts/min of
the radiolabeled DNA probe per sample with binding buffer. Incubations
were carried at room temperature for 10 min. Ten microliters of the 20-µl reaction mixture were electrophoresed on 10%
acylamide/bisacylamide (20:1) gels with 0.5× TBE. Gels were dried and
subjected to autoradiography at 80°C overnight.
Oligonucleotides for EMSA assays. The following sequences were used to produce double-stranded oligonucleotide probes for the EMSA assays: wild type: 5'-GAATGTGTCACCTTCCAGCGTGGAG-3'; mutant: 5'-GAATGTGTCAACTGCCA- GCGTGGAG-3'
Protein measurement. Nuclear extract protein was determined by the Bradford method (9).
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RESULTS |
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Regulation of apo A-IV proximal intestinal mRNA levels by a high-TG
diet.
RT-PCR analysis confirmed a striking increase in jejunal apo A-IV mRNA
levels induced by the high-TG diet, compared with the low-TG diet (Fig.
1). These results are consistent with
those previously reported (7, 8).
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Nuclear runoff assay of apo A-IV transcription.
Nuclear runoff assays confirmed that the pretranslational regulation of
apo A-IV and C-III mRNA levels by dietary lipid in newborn swine
jejunum occurred at the transcriptional level (Fig. 2). Digital densitometry revealed a
3.1-fold increase in apo A-IV gene transcription induced by the high-TG
diet, compared with the low-TG diet.
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Apo A-IV proximal promoter.
Swine apo A-IV proximal promoter (+14 to 246 bp) was cloned and
sequenced. Figure 3 shows swine sequence
compared with human sequence.
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DNAse I DNA protection assay of the proximal apo A-IV promoter.
Footprinting analysis using the swine apo A-IV proximal promoter
sequence and high- and low-TG nuclear extracts demonstrated three
regions protected by the low-TG extracts: AAGGCCG (156 to
150 bp),
ACCTTC (
186 to
181 bp), and CCTCC (
203 to
199 bp) (Fig.
4). Of these three motifs, only ACCTTC
showed 100% homology to the human sequence (Fig. 3) and was further
studied. Extracts from a newborn swine intestinal epithelial cell line
(IPEC-1), untreated with fatty acid, also protected these regions.
Interestingly, nuclear extracts from swine hepatocytes and HeLa cells,
which do not express apo A-IV, also exhibited these same protected
regions.
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EMSA.
When the entire swine apo A-IV proximal promoter sequence was used as a
probe in EMSA analysis using low- and high-TG nuclear extracts in
progressively increasing equivalent amounts, a progressive shift was
noted with the low-TG extracts compared with the high-TG extracts (Fig.
5). This finding suggested that enhanced
protein binding occurred under conditions of low-TG absorption compared with conditions of high-TG absorption.
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DISCUSSION |
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In the present studies, we describe a novel and previously unreported potential mechanism for the transcriptional activation of the apo A-IV gene by dietary lipid in the newborn swine proximal small intestine. Our results suggest that a repressor protein may bind to the ACCTTC motif in the apo A-IV proximal promoter in the absence of dietary lipid flux. This protein appears to dissociate from its binding site on the promoter during lipid absorption, possibly allowing transcriptional activation of the apo A-IV gene in newborn swine small intestine. This regulatory mechanism may be important in the striking induction of jejunal apo A-IV expression by dietary lipid in the neonatal mammal.
Several cis- and trans-acting regulatory elements
have been identified for the apo A-I/C-III/A-IV gene cluster (5,
25). Most of these elements have been described through in vitro
studies using the HepG2 hepatocyte and Caco-2 enterocyte cell lines
and, for the most part, appear to regulate basal and tissue-specific expression of the genes in this cluster. Recently, studies of transgenic mice demonstrated that the upstream 700/
310 fragment of
the apo A-IV gene combined with the
890/
500 apo C-III enhancer is
sufficient to direct a pattern of reporter gene expression similar to
that of the endogenous apo A-IV gene (26). However, responsiveness of reporter gene expression to lipid absorption was not
studied in these animals.
In a few instances, fatty acids have been shown to regulate
transcription of genes in this cluster, as well as other genes involved
in lipid transport and metabolism, through pathways involving specific
transcription factors. Peroxisome proliferator-activated receptors
(PPARs) are polypeptide nuclear receptors related structurally to
members of the steroid/thyroid receptor superfamily. PPARs bind to
specific DNA sequences (PPAR response elements) as heterodimers with
the retinoid X receptor (RXR) to effect transcriptional regulation of
several genes involved in fatty acid oxidation, TG hydrolysis, adipogenesis, cell differentiation, cytokine production, and
inflammation (21). Recently, hepatic nuclear factor-4
(HNF-4), another member of the steroid/thyroid receptor
superfamily, which functions as a transcription activator, has been
shown to be an important regulator of this gene complex. In one report
(20a), fatty acyl-CoA thioesters were shown to bind to
HNF-4 and modulate transcriptional activation. However, the
motif identified in our study does not share similarity with the PPAR
or HNF-4 response elements. Other transcription factors involved in the
expression of the genes in this cluster, including that of apo A-IV,
have not been reported to have any responsiveness to lipid or to bind
to elements with similarity to the sequence of the motif identified in
the present studies, with the exception of retinoid acid receptor-
(RAR-
).
The transcription factor RAR-, which has the binding motif
TsTsACCTyy (where s = G or C and y = C or T), is a possible
candidate for the protein that binds to the (TGTC)ACCTTC motif in the
present studies (3). However, several lines of evidence
suggest that this transcription factor is a very unlikely possibility.
RAR-
is a ligand for 9-cis and all-trans
retinoic acid and usually binds as a homodimer to direct repeats,
palindrome, or inverted palindrome sequences or as a heterodimer with
another nuclear hormone superfamily member, particularly the RXR
(3). RAR-
is not known to be activated by fatty acids.
Furthermore, the ACCTTC motif identified in the swine apo A-IV proximal
promoter in the present study does not have any flanking sequences
identifiable as binding motifs of any transcription factor known to
dimerize with RAR-
.
There are several potential mechanisms by which intestinal lipid absorption may interact with the putative repressor described in this report, as well as with other possible regulatory regions in the apo A-IV/C-III intergenic region, to regulate apo A-IV gene transcription. Luminal lipid may initiate the release of gastrointestinal hormones or other factors that serve as the signal for release of the repressor protein from the promoter. Ileal, but not jejunal, infusion of TG in the adult rat was shown to upregulate apo A-IV expression in ileum and segments of jejunum isolated from the nutrient stream in Thiry-Vella fistulas (23). Massive small bowel resection in rats has also been shown to rapidly upregulate apo A-IV mRNA levels severalfold in remnant ileum within 48 h (31). Therefore, it is possible that factors other than direct uptake of fatty acid by the enterocyte may regulate apo A-IV gene transcription.
Fatty acids derived from dietary TG digestion may exert effects at the enterocyte level via several potential pathways (11). The fatty acid may activate a signal transduction pathway that ultimately alters the DNA binding affinity of the putative repressor protein. Alternatively, the fatty acid may bind to a protein that interacts with the putative repressor, or the fatty acid may bind directly to the repressor protein, thereby altering its DNA binding affinity. Contrary to findings in the adult rat (22), dietary triacylglycerols comprised of medium-chain-length fatty acids are as effective as those containing long-chain-length fatty acids in the induction of apo A-IV mRNA expression in newborn swine jejunum (8). This implies that the fatty acid does not have to be reesterifed to TG in the endoplasmic reticulum to exert its regulatory effect, because medium-chain fatty acids are not reesterified or incorporated into chylomicrons. However, these potential regulatory mechanisms are purely speculative at present.
In summary, we have identified a DNA binding protein that attaches to a unique site on the swine apo A-IV gene proximal promoter under conditions of low dietary TG intake. With a high-TG diet, this protein becomes unbound with a concomitant increase in apo A-IV gene transcription. The binding motif for this protein occurs at three additional sites in the swine apo A-IV/C-III intergenic region, which may also play a role in the regulation of the expression of these genes by dietary lipid in the newborn animal. We suspect that this regulatory mechanism may be specific to the newborn, because the induction of apo A-IV expression is markedly less responsive to dietary lipid near weaning in swine jejunum (7). Efforts are currently underway to isolate and further characterize this putative repressor protein that may play a key role in the regulation of apo A-IV gene expression by intestinal lipid absorption in the neonate.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Child Health and Human Development Grant R01-HD-22551 (to D. D. Black) and by the Children's Foundation Research Center of Memphis at Le Bonheur Children's Medical Center (to D. D. Black).
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. D. Black, Children's Foundation Research Center of Memphis, Le Bonheur Children's Hospital, Rm. 401, W. Patient Tower, 50 N. Dunlap, Memphis, TN 38103 (E-mail: dblack{at}utmem.edu).
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.
First published October 16, 2002;10.1152/ajpgi.00391.2002
Received 11 September 2002; accepted in final form 12 October 2002.
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