(Circulation. 1999;99:2445-2451.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Beneficial Effects of Fibrates on Apolipoprotein A-I Metabolism Occur Independently of Any Peroxisome Proliferative Response
From U325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, France (N.H., P.P., J.C.F., C.F., B.S.); the Department of Clinical Biology, Division of Biochemistry, University of Bergen, Haukeland Hospital, Bergen, Norway (L.M., R.K.B.); the Cardiovascular Department, CRVA Rhône-Poulenc Rorer-Gencell, Vitry-sur-Seine, France (D.B., N.D.); and INRA, Jouy en Josas, France (L.M.H.).
Correspondence to Bart Staels, INSERM U325, Institut Pasteur de Lille, 1, rue du Prof Calmette, 59019 Lille Cedex, France. E-mail bart.staels{at}pasteur-lille.fr
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Abstract |
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Background—In humans, fibrates are frequently used normolipidemic drugs. Fibrates act by regulating genes involved in lipoprotein metabolism via activation of the peroxisome proliferator-activated receptor-
(PPAR) in
liver. In rodents, however, fibrates induce a peroxisome proliferation,
leading to hepatomegaly and possibly hepatocarcinogenesis. Although
this peroxisome proliferative response appears not to occur in humans,
it remains controversial whether the beneficial effects of fibrates on
lipoprotein metabolism can occur dissociated from such
undesirable peroxisomal response. Here, we assessed the influence of
fenofibrate on lipoprotein metabolism and peroxisome
proliferation in the rabbit, an animal that, contrary to rodents and
similar to humans, is less sensitive to peroxisome
proliferators. Methods and Results—First, we demonstrate that in normal rabbits, fenofibrate given at a high dose for 2 weeks does not influence serum concentrations or intestinal mRNA levels of the HDL apolipoprotein apoA-I. Therefore, the study was continued with human apoA-I transgenic rabbits that overexpress the human apoA-I gene under control of its homologous promoter, including its PPAR-response elements. In these animals, fenofibrate increases serum human apoA-I concentrations via an increased expression of the human apoA-I gene in liver. Interestingly, liver weight or mRNA levels and activity of fatty acyl-CoA oxidase, a rate-limiting and marker enzyme of peroxisomal ß-oxidation, remain unchanged after fenofibrate.
Conclusions—Expression of the human apoA-I transgene in rabbit liver suffices to confer fibrate-mediated induction of serum apoA-I. Furthermore, these data provide in vivo evidence that the beneficial effects of fibrates on lipoprotein metabolism occur mechanistically dissociated from any deleterious activity on peroxisome proliferation and possibly hepatocarcinogenesis.
Key Words: apolipoproteins • receptors • lipids • drugs • genes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Fibrates are normolipidemic drugs that decrease triglyceride and increase HDL concentrations in humans.1 Fibrates are efficient drugs for the treatment of specific atherogenic lipid disorders, such as combined hyperlipidemia and hypoalphalipoproteinemia. They exert their effects on plasma lipids by modifying the expression of genes involved in lipoprotein metabolism in the liver.1 In both rodents and humans, fibrates significantly decrease plasma triglycerides. This triglyceride-lowering activity of fibrates is best explained by the increase of lipoprotein lipase2 and the decrease of apolipoprotein (apo) C-III3 gene expression in liver, thereby resulting in enhanced lipolysis of triglyceride-rich particles and subsequent remnant clearance from plasma. The effects of fibrates on HDL metabolism occur primarily via alterations of the expression of the major HDL apolipoproteins, apoA-I and apoA-II, in liver.4 5 6 In contrast to their effects on triglycerides, fibrates influence HDL metabolism in an opposite manner in humans and rodents. In rats, fibrates lower plasma HDL concentrations because of a decrease of liver apoA-I and apoA-II gene expression.7 8 In humans, by contrast, fibrates increase plasma HDL by the induction of both human apoA-I and apoA-II gene expression.4 5 6
Fibrates regulate hepatic expression of these genes via activation of
peroxisome proliferator-activated receptor- (PPAR), a
transcription factor belonging to the nuclear receptor
family.1 After ligand activation, PPAR binds to
specific response elements, called peroxisome proliferator-response
elements (PPREs), in the regulatory regions of target genes, thereby
regulating their expression. Functional PPREs have been identified in
the regulatory regions of the human lipoprotein lipase, apoC-III,
apoA-II, and apoA-I genes.2 4 5 9
In addition to their effects on plasma lipoproteins, fibrates, along
with a number of xenobiotic compounds, also induce a pronounced hepatic
peroxisome proliferation in rodents,10 11 an effect that
is mediated via PPAR.12 Peroxisome proliferation
involves an increase of size and number of peroxisomes through the
induction of specific proteins, most notably the enzymes involved in
peroxisomal ß-oxidation, such as fatty acyl-CoA oxidase
(ACO).13 The peroxisome proliferative response results in
a pronounced hepatomegaly and may ultimately lead to
hepatocarcinogenesis in rodents,11 an observation that is
of major concern, considering the use of fibrates in the long-term
treatment of chronic diseases, such as atherosclerosis,
in humans. However, the magnitude of this response appears to vary
considerably among species, because rodents are more susceptible to
peroxisome proliferation than other species, such as rabbits, nonhuman
primates, and humans (rodents>rabbits>humans). Because PPAR plays
a crucial role in mediating the fibrate response of both lipoprotein
metabolism and peroxisome proliferation in rodent species,
it is important to determine whether the beneficial effects of fibrates
on lipoprotein homeostasis can occur dissociated from a possible
deleterious peroxisome proliferation in humans.
In a previous study using transgenic mice overexpressing the human apoA-I gene, we demonstrated that the species-specific differences in the response of HDL metabolism to fibrates are due to differences in cis-acting elements between the regulatory regions of the human and mouse apoA-I genes.6 Because rodents respond to fibrates by a profound peroxisome proliferation and hepatomegaly, which precede the changes in liver apolipoprotein gene expression and the subsequent effects on lipoprotein metabolism,7 8 this model did not allow us to establish whether the effects of fibrates on apoA-I and HDL occur independently of their effects on peroxisome proliferation. Therefore, we studied the effects of fibrates on apoA-I expression in rabbits, which, like humans, are more resistant to peroxisome proliferation.14 Our results demonstrate that fibrate treatment does not influence serum apoA-I concentrations in normal rabbits. Therefore, we went on to use a transgenic rabbit model that expresses the human apoA-I gene under control of its homologous regulatory regions, including the fibrate-response elements previously shown to be active in mice.6 We show that treatment with fenofibrate increases serum concentrations and liver mRNA levels of human apoA-I in these rabbits. These effects occur without any hepatomegaly or induction of peroxisomal ACO expression and activity in liver, indicating that the beneficial effects of fibrates on lipoprotein metabolism do not require a simultaneous induction of peroxisomal enzyme activities and therefore occur independently.
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Methods |
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Animals
All animal studies were conducted in accordance with institutional guidelines. New Zealand White (NZW) and human apoA-I transgenic rabbits15 were randomized on serum HDL cholesterol and human apoA-I concentrations. Animals were treated daily with fenofibrate (Fournier) mixed with standard chow as indicated. Body weights and food intake were recorded daily. Blood was collected after an overnight fast, and serum was separated and kept at 4°C until analysis. Animals were killed by exsanguination under barbital anesthesia. Tissues were removed, weighed, frozen in liquid nitrogen, and stored until analysis.
Serum Lipid, Apolipoprotein, and Lipoprotein Measurements
Serum triglycerides, total cholesterol,
and HDL cholesterol were measured with kits from
Boehringer Mannheim. Rabbit apoA-I in nontransgenic animals and
total (human and rabbit) apoA-I in transgenic rabbits were quantified
by an immunonephelometric assay.15 Human apoA-I
concentrations were specifically quantified with polyclonal antibodies
raised in rabbit. Interassay coefficients of variation for
cholesterol and apolipoproteins ranged from 1.5% to
6.2%.
Lipoprotein fractions (VLDL, d<1.006 g/mL; IDL+LDL, d=1.006 to 1.063 g/mL; HDL, d=1.063 to 1.21 g/mL) were isolated by sequential ultracentrifugation, and lipoprotein lipid and protein content were measured.
HDL size was determined by nondenaturing gel electrophoresis on 4% to 20% polyacrylamide gradient gels (Novex). Thyroglobulin (665 kDa), ferritin (440 kDa), catalase (232 kDa), lactate dehydrogenase (140 kDa), and albumin (67 kDa) were used as calibrating proteins.
RNA Analysis
RNA isolation and Northern blot analysis were performed
with human apoA-I, rat ACO, and chicken ß-actin cDNA
probes.6 mRNA levels were analyzed by quantitative
scanning densitometry (Biorad GS670 Densitometer) and normalized for
actin levels.
Measurement of Liver ACO Activities
Livers were homogenized in ice-cold sucrose solution
(0.25 mol/L sucrose in 10 mmol/L HEPES buffer and 1 mmol/L
EDTA, pH 7.4), and ACO activity was determined.16
Statistical Analysis
The data from the 3 groups of animals were compared at each time
by ANOVA with the Statview program. When the F ratio was significant
(P<0.05), Wilcoxon paired tests and Mann-Whitney
tests were used for intragroup and intergroup comparisons,
respectively.
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Results |
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Fenofibrate Does Not Influence Liver Weight or ApoA-I Expression in Rabbits
Because the effects of fibrates on serum lipids and, in particular, on serum HDL cholesterol and apoA-I concentrations in rabbits have been poorly characterized, NZW rabbits were treated for 2 weeks with fenofibrate (mixed with chow at 0.625%; consumed doses ranging from 100 to 250 mg · kg-1 · d-1), and serum lipids were measured before and after the treatment period. Serum total cholesterol increased significantly in the fenofibrate-treated animals because of an increase of cholesterol in both HDL and non-HDL particles (Figure 1
). Indeed, the HDL/total
cholesterol ratio was similar in treated and control
animals. Serum triglyceride and apoA-I concentrations did
not change after fenofibrate (Figure 1). Fenofibrate treatment
did not influence intestinal mRNA levels of apoA-I (Figure 1),
whose expression, in contrast to that in humans and rodents, is
restricted to the intestine.17 Therefore, the variations
in serum cholesterol concentrations after fenofibrate
treatment occur independently of transcriptional modulation of apoA-I
gene expression. Furthermore, liver weights did not change after
fenofibrate administration (control, 2.50±0.49% versus treated,
2.38±0.17% of body weight), indicating that the rabbit does not
develop hepatomegaly at doses that induce hepatomegaly in
rats.8
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Fenofibrate Increases Serum Concentrations of HDL and Human ApoA-I
in Human ApoA-I Transgenic Rabbits
To determine whether the presence of the human apoA-I transgene
could confer responsiveness to fibrates in rabbits, human apoA-I
transgenic rabbits were treated with fenofibrate (250 mg ·
kg-1 · d-1) for 3
weeks, and serum concentrations of human apoA-I were measured weekly.
In contrast to untreated transgenic rabbits, whose serum human apoA-I
concentrations remained constant throughout the entire treatment
period, fenofibrate treatment increased human apoA-I >2-fold after 1
week of treatment. Thereafter, human apoA-I concentrations remained
constant, indicating that a steady state is obtained within 7 days of
fenofibrate treatment (Figure 2).
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Next, a dose-response experiment was performed. Human apoA-I transgenic
rabbits were treated for 12 days, at which time maximal effects on
human apoA-I are already observed (Figure 2
), with either 125 or
250 mg · kg-1 ·
d-1 of fenofibrate, and the changes in serum
total and HDL cholesterol, triglyceride, and
human apoA-I concentrations were analyzed. None of the
treatments significantly influenced body weight (Table 1) or food intake of the rabbits (data
not shown). Serum human apoA-I levels significantly increased in a
dose-dependent manner (Table 2 and Figure 3). Whereas total and HDL
cholesterol concentrations decreased slightly in the
untreated rabbits, they increased significantly after fenofibrate
(Table 2 and Figure 3). The changes in HDL
cholesterol were paralleled by similar changes in serum
phospholipids, whereas triglycerides did not change
significantly (data not shown). Because total and HDL
cholesterol concentrations increased to the same extent,
the increase in total cholesterol appeared to be due
primarily to the rise of HDL concentrations after fenofibrate.
Nondenaturing gradient gel electrophoresis analysis revealed no
major change in HDL size distribution after fenofibrate (Figure 4). Furthermore, HDL particle composition
did not differ significantly between control and fenofibrate-treated
animals (data not shown). Thus, fenofibrate increases the number of HDL
particles without affecting their size or composition.
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Fenofibrate Induces Liver Human ApoA-I Without Changing Intestinal
Rabbit ApoA-I Gene Expression
To determine whether the effects of fenofibrate on serum HDL and
human apoA-I were associated with alterations in rabbit or human apoA-I
gene expression, RNA was extracted from livers and intestines and
apoA-I mRNA levels were measured by Northern blot analysis. As
in normal rabbits (Figure 1), fenofibrate did not influence
intestinal rabbit apoA-I gene expression (Figure 5). By contrast, human apoA-I mRNA levels
increased significantly in liver after fenofibrate (Figures 5 and 6). As a control, neither intestinal
or liver actin mRNA levels changed after fenofibrate treatment (Figure 5).
Northern blot analysis indicated the presence of a
single PPAR message of 
8 kb expressed predominantly in liver and
to a lesser extent in intestine, but fenofibrate did not influence
PPAR mRNA levels in either tissue (data not shown).
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Fenofibrate Does Not Influence Liver Weight or Peroxisomal ACO
Activity and mRNA Levels in Human ApoA-I Transgenic Rabbits
To determine whether the effects of fenofibrate on serum HDL and
apoA-I metabolism occur independently of any peroxisome
stimulation, mRNA levels and enzyme activity of ACO, the rate-limiting
enzyme in the peroxisomal ß-oxidation pathway and a sensitive marker
for the PPAR-mediated peroxisome proliferative response to fibrates in
rodents,12 13 18 were measured in human apoA-I transgenic
rabbits treated for 12 days with fenofibrate. Compared with untreated
rabbits, fenofibrate did not significantly increase liver ACO activity
or mRNA levels (Table 1). Furthermore, this treatment did not
induce hepatomegaly (Table 1), as in normal rabbits. Therefore,
the induction of apoA-I expression by fibrates and its consequences on
HDL metabolism occur independently of any peroxisome
proliferative response.
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Discussion |
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Clinical studies in humans have demonstrated that fibrates exert an inductive action on plasma concentrations of HDL, a protective factor against atherosclerosis development.19 Results from both in vitro4 5 and in vivo studies using transgenic human apoA-I mice6 indicate that this HDL induction occurs, in large part, via an increased expression of its major apolipoprotein constituents, apoA-I and apoA-II. Furthermore, the induction of apoA-I and apoA-II expression by fibrates occurs primarily at the transcriptional level and is mediated via PPAR
binding to PPREs in the human apoA-I and
apoA-II gene regulatory regions.4 5 However, because
PPAR also mediates the undesirable peroxisome proliferative response
to fibrates in rodents12 and because most studies on the
effects of fibrates on apolipoprotein gene expression have been
performed in in vitro model systems or in vivo in
rodents,1 it remains highly controversial whether the
beneficial effects on plasma lipoprotein metabolism could
occur independently of a potential hazardous induction of peroxisomal
activity. In the present study, we addressed this issue using the
rabbit as a model for 2 reasons. First, like humans, rabbits have been
reported to be much less responsive to peroxisome proliferators than
rodents.14 Second, our laboratories have recently
established a transgenic rabbit that overexpresses the human apoA-I
gene under control of its homologous promoter, including the
fibrate-response elements.15 These rabbits express the
human apoA-I gene exclusively in the liver, the site of fibrate action,
and carry serum apoA-I concentrations comparable to those in
humans.15
In a first experiment using high concentrations of fenofibrate, we
demonstrated that normal, nontransgenic rabbits are nonresponsive to
fibrate treatment with respect to serum triglyceride and
apoA-I concentrations and intestinal apoA-I mRNA levels. The reason why
rabbits do not respond to fibrate treatment is unclear at present.
Because we (data not shown) and others20 could demonstrate
the presence of PPAR expression in rabbit liver and because the
human apoA-I transgene is responsive to fibrate treatment in rabbits,
absence of functional PPAR expression seems an unlikely explanation.
It is more likely that the absence in rabbit liver of expression of
specific PPAR target genes, such as apoA-I and
apoA-II,21 precludes a fibrate response on these genes in
this species. Indeed, in rabbits, apoA-I expression is limited to the
intestine,17 and fibrates regulate the expression of
apolipoproteins, such as apoA-I and apoA-IV, in the liver and not in
the intestine of rats.7 22 In addition, differences
between species leading to the presence or absence of functional PPREs
in the regulatory regions of genes controlling lipid and lipoprotein
homeostasis may contribute to species-specific differences in response
to fibrates. Indeed, the absence of a functional PPRE in the rat apoA-I
gene promoter contributes to the absence of induction of apoA-I
expression in this species after fibrate treatment.23
In humans or in human apoA-I transgenic mice,6 the elevation of HDL cholesterol after fibrate treatment could be attributed partially to enhanced lipolysis of triglyceride-rich lipoproteins and redistribution of lipid components from these particles to HDL. However, no effect on triglyceride concentrations occurs in fibrate-fed normal or transgenic rabbits. In contrast, fenofibrate treatment resulted in a significant induction of serum total cholesterol concentrations, which was associated with an increase of HDL cholesterol and human apoA-I concentrations. Furthermore, the HDL particles in fenofibrate-treated rabbits were of a size and composition similar to those in untreated transgenic rabbits, suggesting an increased production of HDL rather than alterations in intravascular HDL remodeling after fibrate treatment. These data indicate that, at least in rabbits, the HDL-inductive effects of fibrates are due to the induction of apoA-I expression and occur independently of any triglyceride-lowering activity.
The increase of serum human apoA-I concentrations was associated with a
comparable induction of human apoA-I mRNA levels in liver. In mice, a
disproportionate higher induction of plasma HDL concentrations is
observed after fibrate treatment.6 In contrast to rodents,
rabbits carry a significant portion of their plasma
cholesterol in LDL and have high plasma cholesteryl ester
transfer protein (CETP) activity, similar to that in
humans.24 It is tempting to speculate that the absence of
CETP expression in mice results in an interrupted HDL
metabolism that is exacerbated after fibrate treatment.
Thus, human apoA-I transgenic rabbits may be a better model than mice
for the study of HDL regulation by PPAR and other
activators, because they more closely resemble the human
situation.
The major finding of this study is that serum HDL and human apoA-I increase in human apoA-I transgenic rabbits without any hepatomegaly, indicating that the beneficial effects of fibrates on lipoprotein metabolism occur independently of any deleterious effect on peroxisome proliferation. These results confirm previous studies indicating that rabbits are much less sensitive to peroxisome proliferation than rodents6 8 and more closely resemble the human situation.14 In addition, the absence of hepatomegaly is accompanied by a lack of induction of enzymes of peroxisomal ß-oxidation, such as ACO, whereas serum HDL and human apoA-I concentrations increase significantly after fenofibrate. These observations are in contrast to the situation in rats and (transgenic) mice, in which fenofibrate at doses comparable to those used in this study increases liver weight by >2-fold.6 8 Furthermore, in rats, peroxisomal ACO activity increases to 225% already after a shorter period (5 days) and at lower doses (125 mg · kg-1 · d-1) of fenofibrate, and 5- to 10-fold increases are observed after 2 weeks.25 In primary rat hepatocytes, ACO gene induction by fenofibrate precedes its effects on apolipoprotein gene expression,7 making it impossible to evaluate whether the effects of fibrates on lipoprotein metabolism occur independently of changes in peroxisomal enzyme activities. Here, we show that the induction of human apoA-I gene expression by fibrates occurs independently of any peroxisome proliferative response in vivo. These data extend previous studies in humans suggesting that the hypolipidemic action of fibrates is linked to an increase in mitochondrial but not peroxisomal volume density.26 Furthermore, previous studies in humans revealed no effects of fibrates on liver volume and no influence of fenofibrate or gemfibrozil on liver peroxisomes, whereas clofibrate slightly increased peroxisome number but not size.26 27 28 Furthermore, fibrates do not induce a peroxisome proliferation in human hepatocytes.3 29 Moreover, in human hepatoma HepG2 cells, ciprofibrate treatment did not influence cell morphology or proliferation or ACO activity, whereas rat Fao hepatoma cells responded positively in all these parameters.30 31
Several hypotheses can be offered to explain the absence of peroxisome
proliferation in humans. These include species-specific differences in
the expression level of PPAR or its cofactors in liver
(rodents>humans), differences in ligand specificity of human versus
rodent PPAR leading to a lower response of human PPAR to certain
peroxisome proliferators but not to fibrates, and differences in target
gene specificity. Indeed, the presence/absence of PPREs in target gene
regulatory sequences in the apoA-I gene6 23 may lead to
differences in response between species.
In conclusion, the presence of the human apoA-I transgene is sufficient to confer apoA-I responsiveness to fibrate treatment. Because hepatic peroxisomal enzyme activities are impossible to measure in patients on fibrate therapy, our data obtained in transgenic apoA-I rabbits provide in vivo evidence that the beneficial effects of fibrates on serum lipoprotein metabolism can occur independently of any deleterious peroxisome proliferative effect. Together with several decades of clinical experience showing no evidence of an increased incidence of hepatocarcinogenicity in humans, our results indicate that fibrates should be considered safe drugs with respect to peroxisome proliferation and possibly hepatocarcinogenesis.
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Acknowledgments |
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This work was supported by grants from Institut Pasteur de Lille, INSERM, Rhône-Poulenc Rorer, and the Région Nord-Pas de Calais. We thank O. Vidal, B. Derudas, and J. Frémaux for excellent technical assistance and A. Edgar for discussions.
Received December 21, 1998; accepted January 25, 1999.
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