Received for publication, December 12, 2002, and in revised form, March 11, 2003
The recently discovered APOA5 gene
has been shown in humans and mice to be important in determining plasma
triglyceride levels, a major cardiovascular disease risk factor.
apoAV represents the first described apolipoprotein where
overexpression lowers triglyceride levels. Since fibrates represent a
commonly used therapy for lowering plasma triglycerides in humans, we
investigated their ability to modulate APOA5 gene
expression and consequently influence plasma triglyceride levels. Human
primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a
strong induction of APOA5 mRNA. Deletion and
mutagenesis analyses of the proximal APOA5 promoter firmly
demonstrate the presence of a functional peroxisome
proliferator-activated receptor response element. These findings
demonstrate that APOA5 is a highly responsive peroxisome
proliferator-activated receptor
target gene and support its role as
a major mediator for how fibrates reduce plasma triglycerides in humans.
 |
INTRODUCTION |
Coronary heart disease continues to be a major cause of
morbidity and mortality worldwide. Several epidemiological studies established that, in addition to elevated low density lipoprotein and
reduced high density lipoprotein level, elevated triglycerides (TGs)1 constitute an
independent risk factor for coronary heart disease (1, 2). In addition,
hypertriglyceridemia is often associated with the metabolic syndrome
that characterizes diabetes and obesity (3, 4). Therefore, the
identification of factors or genes affecting triglyceride metabolism is
of significant medical importance for the correction of
hypertriglyceridemia and associated coronary heart disease.
Apolipoproteins play a determinant role in lipoprotein metabolism and
in lipid homeostasis. More specifically, the APOA1/C3/A4 apolipoprotein gene cluster is tightly linked to plasma lipid profiles.
Indeed, mutations in members of this cluster have been shown to cause
severe dyslipidemia and heightened atherosclerosis susceptibility
(5-8). A comparative genomic characterization of the
APOA1/C3/A4 gene cluster flanking regions led to the recent identification of a new apolipoprotein gene, apolipoprotein A5 (APOA5), present in both mice and humans (9). apoAV shares homology with several apolipoproteins, most prominently apoAIV, and is
368 and 366 amino acids long in mice and human, respectively. This gene
appears to be predominantly expressed in the liver and resides on high
density lipoprotein and very low density lipoprotein particles (9,
10).
The properties of apoAV were investigated by creating human
APOA5 transgenic and knock-out mice and by searching for
associations between human APOA5 polymorphisms and plasma
lipid parameters. The Apoa5 knock-out mice display a 400%
increase in plasma triglycerides compared with wild-type mice, while
APOA5 transgenics exhibit triglyceride levels corresponding
to one-third of those in control mice. This determinant link between
APOA5 and triglycerides was supported in several separate
human studies through the consistent demonstration of associations
between APOA5 single nucleotide polymorphisms and plasma
triglyceride levels (9, 11-13). Taken together these mouse and human
studies highlight the importance of APOA5 in the
determination of triglyceride plasma levels, and the clinical relevance
of identifying factors regulating APOA5 expression.
Fibrates are hypolipidemic drugs with pleiotropic effects on lipid
metabolism including the reduction of plasma triglycerides. Classically, the triglyceride lowering action of fibrates is explained by decreased hepatic secretion of very low density lipoprotein and an
enhancement in plasma triglyceride clearance. Several studies established that this effect is mediated through the induction of
lipoprotein lipase expression (14) and down-regulation of APOC3 expression by fibrates (15). A major means by which
fibrates regulate the expression of lipid metabolism-related genes has been shown to be via activation of the peroxisome
proliferator-activated receptor
(PPAR
) (16). Three distinct
PPARs (
,
, and
) have been described in different species
(17). PPARs are ligand-activated nuclear receptors that dimerize with
the retinoid X receptor (RXR) and bind to specific DNA sequence defined
as peroxisome proliferator response elements (PPREs). Upon binding,
PPARs activate gene transcription.
Given the determinant link between APOA5 and plasma
triglycerides and the widespread use of fibrates in the treatment of
dyslipidemia, we investigated whether fibrates can modulate
APOA5 gene expression and consequently influence plasma
triglyceride levels. Our studies with human hepatocytes revealed that
fibrates dramatically increase APOA5 expression. Coupled
with in vitro promoter analysis and the demonstration of a
functional APOA5 PPRE, these data identify fibrates acting
via PPAR
as a crucial regulator of the new apolipoprotein APOA5 and suggest a novel clinical mechanism for how PPAR
activators can influence triglyceride homeostasis.
 |
EXPERIMENTAL PROCEDURES |
Cloning and Construction of Recombinant Plasmids--
Exon 1 of
the human and mouse APOA5 gene were determined by
examination of the expressed sequence tag data base and identification of numerous cDNA clones that terminate at a common 5' base pair in
the genome sequence. The four exon structure of APOA5 is
consistent with that of the evolutionarily related apolipoprotein genes
(APOA1, APOC3, and APOE). Human
APOA5 promoter fragments (
846/+62,
305/+62,
147/+62)
were amplified by PCR using a APOA5 genomic BAC clone (9) as
template and cloned in pGL3 luciferase vector. The followed forward oligonucleotides 5'-AGACCTGTTGGAGGCTATGAATGC-3',
5'-TCTGTTGGGGCCAGCCAG-3', 5'-GGTGCCAGGGAAAGGGCAGG-3', and the reverse
oligonucleotide 5'-AATGCCCTCCCTTAGGACTGTGAC-3' primer were used for the
PCR reaction. Site-directed mutagenesis (Stratagene) of the
APOA5 promoter was accomplished using the oligonucleotide
5'-AGTGGGAAGCTTAAAGATCATGGGGTT-3' as a mutagenic primer. The human APOA5-PPRE
(5'-GATCCGGGAAGGTTAAAGGTCATGGGA-3') site oligonucleotide was cloned in
tandem repeat into BamHI/BglII sites of pIC20H,
digested with HindIII, and subcloned upstream of the
thymidine kinase (TK) promoter of pBLCAT4 as described previously
(18).
Cell Culture and RNA Analysis--
Primary human hepatocytes
were isolated, maintained, and treated with fibrates as described
previously (18). RNA preparation and Northern blot hybridizations were
performed as described previously (9). The 0.9-kb APOA5
cDNA probe was amplified by PCR with full-length APOA5
cDNA as template and the oligonucleotides
5'-GATAATGGCAAGCATGGCTG-3' and 5'-CTGCAGGTAGGTGTCCTGGCGGA-3' and
subcloned in pBS-SK+.
Transfections and Transient Expression Assay--
Human hepatoma
HepG2 cells were maintained and transiently transfected by calcium
phosphate coprecipitation as described (18) using 0.3 µg of reporter
vector, 30 ng of PPAR
expression vector, and 30 ng of
CMV-
-galactosidase expression vector as a control for transfection efficiency.
Gel Retardation Assay--
mPPAR
and mRXR
proteins were
synthesized in vitro using the rabbit reticulocyte lysate
systems (Promega). Gel retardation assays were performed as described
previously (18).
 |
RESULTS |
Human APOA5 Gene Expression Is Induced by Fibrate Treatment in
Human Primary Hepatocytes--
To determine whether fibrates can
modulate APOA5 gene expression in humans, we analyzed
APOA5 mRNA levels in primary human hepatocyte upon
treatment with fenofibric acid, the active form of fenofibrate, or Wy
14,643, a prototype PPAR
agonist. Treatment with fenofibric acid at
a concentration (100 µM) (similar to that reached in
plasma from treated patients) dramatically induced APOA5
mRNA levels (about 5-fold increase). We observed a similar effect
with Wy 14,643 treatment (Fig. 1). These
observations demonstrate that fibrates induce the expression of human
APOA5, suggesting APOA5 as a new target gene for
fibrates.

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Fig. 1.
Effect of fenofibric acid and Wy 14,643 on
human APOA5 expression. Human hepatocytes were isolated and
treated 24 h with fenofibric acid (100 µM), Wy
14,643 (100 µM), or vehicle (Me2SO) as
indicated. Total RNA (10 µg) was subjected to Northern blot analysis
using human APOA5 cDNA (top panel) or human
acidic ribosomal phosphoprotein 36B4 (bottom panel) cDNA
probes.
|
|
Gene Regulation of APOA5 by Fibrates Occurs at the Transcriptional
Level--
To determine whether APOA5 was directly
responsive to PPAR, we examined the proximal APOA5 promoter
for potential PPRE sites (Fig. 2).
Upstream of exon 1 a consensus TATAA and CAATT box were readily
apparent, as was a putative PPRE site (
272/
260). To delineate the
mechanism of regulation of APOA5 gene expression by
fibrates, we performed functional analysis of the APOA5
promoter. HepG2 cells were transiently transfected with a
luciferase reporter vector driven by different human
APOA5 promoter fragments (from
846/+62,
305/+62,
147/+62). Cotransfection with PPAR
strongly stimulated the
APOA5 promoter activity (about a 25-fold increase with
construct
846/+62 and about a 40-fold increase with construct
305/+62) in the presence of Wy 14,643 (Fig.
3). Transcriptional activity of the
APOA5 reporter construct was also slightly induced by the
addition of Wy 14,643 in the absence of cotransfected PPAR
. Deletion
analysis of the promoter located a putative PPRE between nucleotides
305 and
147 from the initiation start site. These results support
that the gene regulation of APOA5 by fibrates occurs at the
transcriptional level.

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Fig. 2.
Sequence upstream of the putative APOA5
promoter. Exon 1 is depicted by a white box with the
start site of transcription indicated by +1. Consensus sites
for a CAAT and TATAA box are bold and underlined,
as well as a predicted PPRE-DR1 site ( 272/ 260).
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Fig. 3.
Delineation of the PPRE in the human APOA5
promoter. HepG2 cells were transfected with different human
APOA5 promoter fragment reporter plasmids ( 846/+62,
305/+62, 147/+62) cloned into luciferase reporter vector.
Cells were cotransfected with empty vector pCMV or pCMV-mPPAR and
incubated with Wy 14,643 (1 µM) (black bars)
or vehicle (Me2SO (DMSO), white bars)
for 48 h. Luciferase activity is expressed as means ± S.D.
Luc, luciferase.
|
|
APOA5 Contains a PPRE That Confers Responsiveness to
PPAR
--
Transcriptional activation of APOA5 gene by
PPAR
suggests the presence of a functional PPRE in the
APOA5 promoter. Sequence analysis revealed the presence of a
putative PPRE with a high degree of homology between
APOA5-PPRE and the PPRE consensus defined for PPARs (19). To
assess whether the putative PPRE mediates the PPAR
effect, we
performed transfection experiments using
305/+62 promoter construct
containing a mutated version of the PPRE. The mutation is designed to
suppress the binding of PPAR as described previously (18). Mutation of
the PPRE abolished the activation of the APOA5 promoter by
PPAR
(Fig. 4).

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Fig. 4.
Identification of the APOA5-PPRE by mutation
analysis. HepG2 cells were transfected with human APOA5 promoter
reporter construct ( 305/+62) or with a construct containing a
mutation (cross) of the putative PPRE. Cells were
cotransfected with empty vector pCMV or pCMV-mPPAR and incubated
with Wy 14,643 (1 µM) (black bars) or vehicle
(Me2SO (DMSO), white bars).
Luciferase activity is expressed as means ± S.D. Luc,
luciferase.
|
|
To prove that the putative APOA5-PPRE could function as a
PPRE, we cloned it in three oriented copies in front of heterologous promoter TK and challenged with PPAR
in HepG2 cells. We found that
this site could transmit PPAR
activation (about 5.8-fold increase in
the presence of PPAR
and Wy 14,643) to the TK promoter (Fig.
5A). We performed electrophoretic
mobility shift experiments to examine whether PPAR-RXR heterodimer
could bind to the PPRE. Incubation of labeled PPRE oligonucleotide with
in vitro translated PPAR
and RXR
resulted in the
formation of a strong retarded complex (Fig. 5B). Taken
together these results demonstrate that APOA5 promoter
contains a functional PPRE that confers PPAR
activator responsiveness.

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Fig. 5.
APOA5-PPRE transmits activation to the TK
promoter and binds PPAR . A,
HepG2 cells were transfected with APOA5-PPRE(×3) in front
of a TK promoter (pBL-CAT reporter) with empty vector pCMV or
pCMV-mPPAR and incubated with Wy 14,643 (1 µM)
(black bars) or vehicle (Me2SO
(DMSO), white bars). CAT activity is expressed as
means ± S.D. B, gel retardation assays were performed
with radiolabeled oligonucleotides in the presence of in
vitro translated mPPAR and mRXR . CAT,
chloramphenicol acetyltransferase; Lys, unprogramed rabbit
reticulocyte lysate.
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|
 |
DISCUSSION |
Fibrates are among the most effective agents for lowering plasma
triglycerides in humans. In this report, we show that fibrates dramatically affect the expression of the recently identified APOA5 gene in humans. The previous studies demonstrating
that apoAV is selectively produced by the liver and behaves as a
regulator of plasma triglyceride levels, coupled with the results of
the present study, argue in favor of a crucial link between fibrates, APOA5, and triglyceride metabolism. The up-regulation of
human APOA5 is important regarding of the molecular
mechanism of triglycerides homeostasis action of fibrate. Indeed,
APOA5 represents to date the first example of an
apolipoprotein whose overexpression leads to a decrease in triglyceride
levels (9, 20), whereas APOC3 or another apolipoprotein
transgene leads to an increase in triglycerides plasma levels
(21-24).
The activation of APOA5 transcription may be attributed to a
PPRE located inside the proximal APOA5 promoter. Remarkably, this PPRE differs 1 nucleotide from the consensus PPRE ((AGGTCA) A
(AGGTCA)) or DR-1 (direct repeat 1). Binding and functional studies indicate that this PPRE confers a significant PPAR
-mediated transactivation. The rate of transcriptional up-regulation induced by
PPAR
activation on APOA5 is among, if not the highest,
level attained for genes regulated by fibrates studied in human primary hepatocyte model (APOA2 (18) and CPT-1 (25)).
Actually, gene regulation via PPREs is complex. Indeed, the DR-1
structure of the PPRE can integrate different antagonistic actions
induced by nuclear receptors such as RXR, retinoic acid receptor (RAR)
(26), HNF4, and ARP-1 (or COUP-TF) (27) depending on the sequence of
the regulatory element and the context of the promoter. The
APOC3 gene harbors one DR-1 that can bind PPAR/RXR heterodimer, but its promoter responds to PPAR only in non-hepatocyte cells (26), whereas HNF4 (28) or RXR induce transactivation (26).
Fibrates down-regulate APOC3 gene expression probably through indirect inhibition of the HNF4 nuclear receptor (29). Alternatively, PPAR
activators stimulate Rev-erb
(30) that in
turn represses APOC3 (31). Therefore, APOA5 is
the first triglyceride lowering apolipoprotein gene that is firmly
identified as a positive and a direct target gene of PPAR
activators.
So far, most of the TG lowering effects have been mainly attributed 1)
to the induction of lipoprotein lipase gene expression, which enhances
catabolism of TG-rich particles (14), and 2) to the down-regulation of
APOC3 gene (15), leading to a decreased hepatic very low
density lipoprotein secretion. The exact contribution that alterations
in expression of these genes have on plasma triglyceride levels is not
known but appears to be dependent on the activation by PPAR
.
Analysis of the APOA5 transgenic and knock-out mice showed
that their changes in plasma triglyceride levels were directly opposite
to those previously reported for the APOC3 knockout and transgenic mice (21, 22). The Apoa5 knock-outs display a
400% increase in plasma TG compared with the 30% decrease observed in
Apoc3 knock-outs, whereas APOA5 transgenic showed
decreased triglyceride levels compared with the increase reported in
APOC3 transgenics. In addition, overexpression of
APOA5 was accompanied by a lowered apoc3 protein level (9).
Therefore, APOA5 may be defined as a major determinant of
triglyceride levels and from the present study appears to be fibrate
responsive through action of PPAR
. Based on the magnitude of the
effect that altered APOA5 expression has on plasma
triglycerides in mice compared with APOC3, APOA5
may be defined as a potentially major determinant of triglyceride homeostasis. The results of the present study convincingly demonstrate that APOA5 is a target gene for PPAR
activators. This
gene regulation of APOA5, combined with the dramatic effects
previously shown in APOA5 transgenic and knock-out mice on
plasma triglyceride levels, suggest a plausible explanation for the
ability of PPAR
activators to lower plasma TG levels. Modulation of
APOA5 via a PPAR
pathway offers a new strategy for
intervention designed at correcting hypertriglyceridemia and at
limiting TG-associated metabolic disease and cardiovascular risk.
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