# Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

Authors: Sander Kersten
Journal: PPAR Research
 (2008)

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## Abstract

Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARα is the molecular target for the fibrate class of drugs. Activation of PPARα in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPARα activation in humans. PPARγ is the molecular target for the thiazolidinedione class of drugs. Activation of PPARγ in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.


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## Body

## 1. Introduction

Plasma
lipoproteins are responsible for carrying triglycerides and cholesterol in the
blood and ensuring their delivery to target organs. Extensive research over the
past few decades has demonstrated that elevated plasma levels of
cholesterol-rich low-density lipoproteins (LDLs) are associated with increased
risk for coronary heart disease, whereas elevated levels of high-density
lipoproteins (HDLs) have a protective effect. Accordingly, raising HDL levels
and especially lowering LDL levels has become the cornerstone for the
nutritional and pharmacological prevention and treatment of coronary heart
disease. While lowering of plasma LDL can be efficiently and adequately
achieved by treatment with statins, limited pharmacological treatment options
are available for efficiently raising HDL levels. Hence, the quest for
effective and safe drugs that raise HDL levels and/or decrease the atherogenic
properties of plasma lipoproteins continues. A group of proteins that plays a
major role in the regulation of lipoprotein metabolism and can be considered as
major drug targets for correcting abnormal plasma lipoprotein levels are the
nuclear receptors [1]. Nuclear receptors are
ligand-activated transcription factors that alter gene transcription by direct
binding to specific DNA response elements in target genes [2]. In addition, they modulate
transcription by interfering with specific intracellular signaling pathways,
thereby impairing transcriptional activation by other transcription factors.
Nuclear receptors share a common modular structure that includes a relatively
well-conserved central DNA-binding domain and a C-terminal ligand binding
domain (LBD) [2]. Several nuclear receptors
have been shown to be involved in the regulation of plasma lipoprotein
metabolism, including the estrogen receptors (ERs), the oxysterol receptors
(LXRs), the bile acid receptor (FXR), and the fatty acid receptors (PPARs).
Here, the emphasis will be on the role of PPARs.The PPAR family includes three
members encoded by distinct genes:α, β/δ, and γ [3]. Since the initial discovery
of the PPARα isotype in 1990 [4], an impressive amount of
literature on these receptors has accumulated. PPARs mainly operate by
governing the expression of specific sets of genes. Analogous to many other
nuclear receptors, PPARs bind to DNA and regulate transcription as a
heterodimer with the retinoid X receptor (RXR) [5]. The genomic sequence
recognized by PPARs, referred to as PPAR response element or PPRE, consists of
a direct repeat of the consensus hexameric motif AGGTCA interspaced by a single
nucleotide. Functional PPREs have been identified in genes involved in a
variety of biological processes including lipid and glucose metabolism, detoxification,
and inflammation [6]. Activation of transcription
by PPARs is achieved by binding of specific ligands to the LBD, followed by
recruitment of coactivator proteins and dissociation of corepressors. Coactivator
recruitment generally leads to an increase in enzymatic activity of histone
acetyltransferases, histone methyltransferases, and subsequent nucleosome
remodeling, activities which are essential to initiate transcription of PPAR
target genes. X-ray crystallographic analysis of the LBD of PPARs has revealed
an exceptionally spacious ligand binding pocket that can be occupied by a wide
variety of synthetic and natural agonists, including numerous fatty acids and
fatty acid-derived eicosanoids [7, 8].The
three PPARs are distinguishable by specific tissue and developmental patterns
of expression and by their activation by distinct, yet overlapping, ligands [9]. The PPARα
isotype is well expressed in tissues such as liver, heart, and small intestine
and regulates a variety of target genes involved in cellular lipid metabolism
ranging from mitochondrial, peroxisomal, and microsomal fatty acid oxidation to
fatty acid uptake and binding, lipolysis, lipogenesis, and glycerol metabolism [6]. In contrast, PPARγ,
which is highly expressed in brown and white adipose tissue, directs the
expression of genes involved in adipocyte differentiation and fat storage. In
addition, PPARγ governs glucose uptake and storage [10]. Much less is known about the
ubiquitously expressed PPARβ/δ, although recent evidence suggests an
involvement in wound healing [11], fatty acid oxidation [12], and lipoprotein metabolism [13].Here
we present an overview of the literature on PPARs and lipoprotein metabolism.
The emphasis is on physiological role of PPARs and the mechanisms underlying
the effect of synthetic PPAR agonists on plasma lipoproteins.


## 2. PPARα and Plasma Triglyceride Metabolism

The seminal evidence
that placed PPARα at the center of lipoprotein metabolism
was the demonstration that fibrates, which had been used clinically for many
years to treat dyslipidemia, act by binding to PPARα and
induce PPARα-dependent gene transcription [4, 14]. The role of PPARα in
lipoprotein metabolism could thus be extrapolated retrospectively by analyzing
the reported effect of fibrates. The availability of PPARα
null mice further spurred progress in elucidating PPARα function
and has resulted in an extensive picture of the role of PPARα in
lipoprotein metabolism [15].Numerous
clinical studies in humans have provided ample evidence that fibrates, which
include clofibrate, bezafibrate, fenofibrate, and gemfibrozil, effectively
lower fasting plasma triglycerides (TG) [16–19]. The plasma TG lowering
effect of fibrates can be reproduced in mice [20, 21].  Conversely, plasma TG levels are elevated in mice
lacking PPARα [22]. Since in the fasted state
plasma TG are carried mainly in the form of very low-density lipoproteins
(VLDL), this suggests that PPARα suppresses VLDL production in liver
and/or stimulates clearance of VLDL triglycerides in peripheral tissues.


## 3. PPARα and VLDL Production

Limited data are
available on the effect of fibrates on production and secretion of VLDL in
humans. In one study, the PPARα agonist gemfibrozil decreased
production of VLDL-TG, while clofibrate had no effect [23]. In mice, PPARα has
been shown to have a major impact on hepatic TG secretion. Indeed, deletion of
PPARα is
associated with a significant increase in VLDL-TG production in liver [24, 25]. In contrast, activation of
PPARα using
Wy14643 dramatically lowers VLDL-TG production (Figure 1). Furthermore, activation
of PPARα suppresses TG secretion from primary
rat hepatocytes [26].The PPARα agonist Wy14643 dramatically lowers VLDL production in a mouse model of
hypertriglyceridemia. Male Angptl4-transgenic mice (n=7 per group) were given
vehicle or Wy14643 for 10 days (0.1% mixed in their food). After a 24-hour fast,
the LPL-inhibitor tyloxapol (Triton WR1339, 500 mg/kg bodyweight as 15%
solution in saline) or saline were injected intraorbitally. (a) Plasma
triglyceride concentration was measured every 30 minutes to determine the VLDL
production rate. (b) Mean rate of increase of plasma TG concentration in mice
that received tyloxapol. Differences were evaluated by Student’s t-test (P***<.001).
Error bars represent SEM.
(a)(b)VLDL
is synthesized by the stepwise lipidation of the structural component
apolipoprotein B through the action of microsomal triglyceride transfer protein
(MTTP), resulting in the gradual formation of a mature TG-rich VLDL1 particle [27]. It may be expected that
elevated hepatic TG levels increase VLDL secretion, on the one hand by
targeting apolipoprotein B away from degradation toward secretion, thus
increasing VLDL particle number, and on the other hand by increasing the amount
of TG that becomes incorporated into VLDL, thus increasing VLDL particle size [27–29].
However, a positive correlation between hepatic TG and VLDL production is not
always evident, as illustrated by the lack of change in hepatic VLDL production
in ob/ob mice despite massive steatosis [30].
These data feed a growing recognition that the relation between hepatic TG
storage and VLDL production is dependent on where the excess TG are stored.
This argument holds both at the tissue level, as only excess TG stored in
the periportal area may promote VLDL formation,  and at the cellular level, as TG incorporated into VLDL are likely drawn
from specific intracellular lipid compartments.Numerous
studies have shown that PPARα activation lowers liver TG
levels, especially in the context of a fatty liver [31–36]. Conversely, deletion of PPARα is
associated with elevated hepatic TG stores, which is evident under normal fed
conditions but becomes considerably more pronounced after prolonged fasting and
chronic high fat feeding [22, 37–40].  The potent effect of PPARα
activation and deletion on hepatic TG levels is illustrated in Figure 2.
Remarkably, treatment of wildtype but not PPARα null mice with Wy14643 for 10 days can
completely prevent the fasting-induced increase in hepatic TG, most likely by
stimulating fatty acid oxidation. Indeed, probably the best understood property
of PPARα is its ability to stimulate fatty acid
oxidation by upregulating almost every single gene within the mitochondrial,
peroxisomal, and microsomal fatty acid oxidation pathway, including carnitine
palmitoyl transferase 1 and 2, acyl-CoA oxidase, acyl-CoA dehydrogenases, and
numerous others [6]. Many of these genes have
been identified as direct PPARα targets characterized by the presence
of a functional PPRE. Accordingly, the most plausible explanation for the
hepatic TG lowering effect of PPARα activation is that by promoting fatty
acid oxidation, PPARα shifts fatty acids away from
esterification and storage. While its effect on fatty acid oxidation likely
accounts for the major share of its antisteatotic action,  regulation of other
genes and pathways by PPARα may contribute to some extent as well.The PPARα
agonist Wy14643 prevents the fasting-induced increase in liver TG levels. Male
wild-type and PPARα null mice (n=5 per group) were given
vehicle or Wy14643 for 10 days (0.1% mixed in their food). After a 24-hour fast,
livers were dissected and stained histochemically using hematoxylin/eosin (a)
or oil Red O (b). Representative livers sections are shown. Differences
visualized by histochemistry were perfectly confirmed by quantitative
measurement of hepatic TG levels.
(a)(b)Suppression
of VLDL production by PPARα agonists is generally attributed to
lowering of hepatic TG stores, despite uncertainties surrounding the
relationship between hepatic TG storage and VLDL production. In addition to its
role in fatty acid catabolism, PPARα impacts on multiple aspects of
intracellular lipid trafficking and metabolism, some of which may oppose
hepatic TG lowering, including induction of genes involved in fatty acid
synthesis and fatty acid elongation/desaturation [41–44]. Furthermore, expression of
MTTP, which is involved in the lipidation of apoB100 to form a nascent VLDL
particle, has recently been shown to be increased by PPARα [21]. Upregulation of MTTP may
promote apoB100 secretion, which together with a decreased TG availability may
favor the targeting of apoB100 to IDL and LDL rather than VLDL [21]. Interestingly, a recent
study points to adipose differentiation-related protein (ADRP), which is a
direct target gene of PPARα [45], as a potential mediator of
the effect of PPARα on VLDL production. Using cultured
cells it was shown that an increase in ADRP prevents the formation of VLDL by
diverting fatty acids from the VLDL assembly pathway into cytosolic lipid
droplets [46]. It can be expected that as
the process of VLDL assembly and secretion becomes better understood and the
role of PPARα in this process is further clarified,
the general view on the mechanism underlying the effect of PPARα on
hepatic VLDL secretion may change.


## 4. PPARα and VLDL-TG Clearance

Several studies have
examined the impact of PPARα on clearance of TG-rich lipoproteins in
humans, all of which show increased clearance after treatment with PPARα
agonists [23, 47–49]. Clearance of VLDL-TG from
plasma is mediated by the enzyme lipoprotein lipase (LPL) which thus has a
critical role in determining plasma TG concentrations.  LPL is synthesized
mainly by adipocytes and myocytes, and after translocation to capillary
endothelial cells it is anchored into the vessel wall via
heparin-sulphate proteoglycans. Treatment of human subjects with PPARα
agonists is associated with a significant increase in postheparin total LPL
activity, suggesting that stimulation of plasma TG clearance by PPARα
agonists can be attributed to enhanced LPL activity [49–51].Theoretically,
changes in LPL activity can be achieved by altering the production of LPL
itself, or by altering the production of proteins that assist with LPL function
or modulate its enzymatic activity. The latter group includes apolipoproteins
such as APOC3, APOC2, and APOA5, as well as angiopoietin-like proteins 3 and 4.
While it is clear that expression of LPL is upregulated by PPARα in
liver [52], no evidence is available
indicating a role for PPARα in governing LPL expression in heart
and skeletal muscle. According to our unpublished microarray data, neither PPARα
deletion nor 5-day treatment with Wy14643 had any influence on LPL mRNA
expression in mouse heart. It thus appears that rather than by regulating
expression of LPL itself, PPARα agonists stimulate plasma TG clearance
by altering the hepatic expression of inhibitors or activators of LPL activity.
In both mouse and human, hepatic mRNA expression and plasma levels of APOC3,
which inhibits LPL activity, are lowered by PPARα agonists [53–56]. Several mechanism have been
put forward to explain downregulation of APOC3 expression by PPARα,
involving the transcription factors Rev-erbα, HNF4α, or FOXO1 [57–60]. In contrast to APOC3, PPARα
agonists increase hepatic expression and plasma levels of APOA5, an activator
of LPL [61]. A functional PPAR responsive
element has been identified in the promoter of the human APOA5 gene,
classifying APOA5 as a direct PPARα target gene [62, 63].It
can be hypothesized that the stimulatory effect of PPARα on
clearance of TG-rich lipoproteins may be counterbalanced by PPARα-dependent
upregulation of the LPL inhibitor Angptl4 [64, 65]. Plasma levels of Angptl4 are
increased by fenofibrate treatment [66]. Data obtained from various
transgenic mouse models and from human genetic studies indicate that Angptl4
inhibits the clearance of TG-rich lipoproteins, likely by stimulating the
conversion of catalytically active dimeric LPL to catalytically inactive
monomeric LPL [67–72]. It can be speculated that upregulation
of Angptl4 may explain the inhibitory effect of PPARα
agonists on LPL activity in macrophages, adipose tissue, and cardiomyocytes [73–76].


## 5. PPARα and HDL Metabolism

In addition to
their plasma TG-lowering effect, fibrates are used clinically for their ability
to raise plasma HDL-cholesterol (HDLc) levels. A recent meta-analysis of 53
clinical trials indicates that on average, fibrates elevate plasma HDLc levels
by about 10%, which translates into a 25% reduction in risk for major coronary
events [77]. Remarkably, this effect is
not observed in rodents, which seriously complicates study of the molecular
mechanisms underlying the effect of PPARα agonists on HDL. In mice, plasma total
cholesterol and HDLc levels are reduced by treatment with synthetic PPARα
agonists [78], whereas levels are increased
in mice lacking PPARα [20]. The differential effects of
PPARα on
plasma HDL between mouse and human is likely due to species-specific regulation
of apolipoprotein A-I (APOA1), the core apolipoprotein of HDL. Whereas
PPARα activation increases plasma levels and
hepatic mRNA expression of APOA1 in human, as supported by studies using human
APOA1 transgenic mice and human hepatocytes [79], the opposite effect is
observed in rodents [78]. The lack of upregulation of
APOA1 gene expression by PPARα in rat was attributed to 3 nucleotide
differences between the rat and the human APOA1 promoter A site, rendering a
positive PPAR-response element in the human APOA1 promoter nonfunctional in
rats [80]. In addition to APOA1, plasma
levels and hepatic mRNA expression of APOA2, another major apolipoprotein
component of HDL, are also increased by fibrates in humans [51, 81]. In contrast, in rodents both
a reduction and induction of APOA2 expression after treatment with fibrates
have been observed [20, 78].In
recent years, our knowledge regarding the mechanisms and location of HDL
formation has improved considerably. Recent evidence suggests that the
intestine and liver are responsible for the major share of HDL synthesis [82, 83]. It is generally believed
that HDL is formed by lipidation of lipid poor APOA1 mediated by the
cholesterol efflux transporter ABCA1. The importance of ABCA1 in HDL synthesis
is illustrated by the almost complete absence of HDL from plasma of patients
with a dysfunctional ABCA1 gene [84]. This metabolic abnormality
is reproduced in mice that lack ABCA1 [85, 86]. Importantly, the expression
of ABCA1 is increased by PPARα in intestine and macrophages [87, 88]. No PPRE has yet been
identified in the human or mouse ABCA1 gene, suggesting that ABCA1 may not be a
direct PPARα target. Instead, upregulation of ABCA1
mRNA by PPARα agonists in macrophages likely occurs
via PPARα-dependent upregulation of LXR, which is
a transcriptional activator of ABCA1 [88, 89]. Whether the same mechanism
operates in intestine remains unclear.Recently,
ABCG1 was identified as the transporter responsible for cellular efflux of
cholesterol towards mature HDL [90]. So far no evidence is
available that suggests regulation of ABCG1 by PPARs.Several
proteins are involved in HDL remodeling including lecithin cholesterol acyltransferase
(LCAT), phospholipid transfer protein (PLTP), and cholesteryl ester transfer
protein (CETP). In mice, fibrates decrease plasma LCAT activity and hepatic
LCAT mRNA  expression [91]. Hepatic expression and
plasma activity of PLTP, which increases HDL particle size by catalyzing the
transfer of phospholipids from VLDL/IDL to HDL, are increased by PPARα in
wild-type but not PPARα null mice. Accordingly, upregulation of
PLTP may account for the observed increase in HDL particle size in mice treated
with fibrates [92]. Since CETP is absent from
mice, the role of PPARα in the regulation of CETP activity has
largely remained elusive. Interestingly, in a recent study using
hCETP-transgenic mice on an apoE3 Leiden background, it was found that
fenofibrate markedly reduced CETP activity in parallel with an increase in plasma
HDLc levels [93]. These data imply that
fibrates reduce CETP activity in humans, suggesting that the effect of fibrates
on plasma HDL levels in humans may be partially achieved by suppressing CETP
activity. In addition, it can be speculated that as PPARα
activation decreases plasma VLDL levels, the acceptor pool for the
CETP-catalyzed exchange of cholesterol-esters with HDL will be diminished,
resulting in increased HDL size.HDL
cholesterol can also be cleared by the SCARB1-mediated selective removal of
cholesterol from the HDL particle, or by endocytic uptake and degradation of
the whole particle, called holoparticle HDL uptake. A possible mechanism by
which fibrates may impair HDL clearance is by downregulating hepatic SCARB1
gene expression in a PPARα dependent manner [94].


## 6. PPARβ/δ and Lipoprotein Metabolism

While the role
of PPARα in the regulation of lipoprotein
metabolism is relatively well characterized, much less is known about PPARβ/δ. Initial
studies in mice showed that selective PPARβ/δ agonists raise plasma HDLc levels [13, 95]. The HDLc-raising effect is
also evident in rhesus monkeys [96], and, according to a recent
report, in human subjects [97]. In monkey and human, but
seemingly not in mice, PPARβ/δ agonists decrease plasma TG levels as
well. The mechanism behind the HDLc-raising effect of PPARβ/δ
agonists remains obscure, although a role for ABCA1, which is upregulated by
PPARβ/δ,
has been proposed [96].In
line with the plasma TG-lowering effect of PPARβ/δ agonists observed in primates, plasma
TG levels are elevated in PPARβ/δ null mice [98]. In contrast, plasma total
cholesterol and HDLc remain unchanged. It was proposed that the elevated plasma
TG levels in PPARβ/δ null mice are caused by a combination
of increased VLDL production and decreased plasma TG clearance, as evidenced by
a decrease in postheparin LPL activity and increased hepatic expression of LPL
inhibitors Angptl3 and 4. Overall, insight into the molecular mechanisms that
may underlie the observed changes in plasma lipoproteins is lacking, which is
partly due to the fact that very few PPARβ/δ specific or selective target genes are
known. Since PPARα agonists also increase plasma HDLc
levels, it might be hypothesized that PPARβ/δ agonists might act via common molecular
targets. However, at least in mice, PPARα and PPARβ/δ agonists display divergent effect on
plasma TG levels, suggesting a different mode of action.


## 7. PPARγ and Plasma Triglyceride Metabolism

Synthetic PPARγ
agonists are prescribed for their ability to promote insulin sensitivity and
lower plasma glucose levels in patients suffering from type 2 diabetes mellitus
(T2DM). On top of an insulin-sensitizing action, numerous studies in mice and humans
have shown that use of PPARγ agonists leads to a reduction in fasting
and postprandial plasma TG levels [99–103]. Some variability in the
plasma TG lowering effect is observed between different PPARγ
agonists, and in mice between various disease models. Indeed, no effect of PPARγ
agonists on plasma TG is observed in the two mouse models most commonly used
for atherosclerosis research, which are the LDL receptor knock-out and apoE
knock-out mice [104]. In humans rosiglitazone
seems to specifically lower postprandial but not fasting TG levels [105, 106]. Evidence has been provided
that the plasma TG lowering effect of PPARγ agonists may be connected to their
insulin sensitizing action by suppressing adipose tissue lipolysis and plasma
FFA levels, which is expected to lead to decreased hepatic VLDL-TG production [106]. However, no relationship exists
between the insulin-sensitizing potency of PPARγ agonists and plasma TG lowering [107]. Furthermore, in a recent
study, treatment of type 2 diabetic subjects with pioglitazone did not result
in any change in hepatic VLDL-TG production
[108]. Thus, whereas PPARα
agonist lowers plasma TG by a combination of suppressing hepatic VLDL
production and stimulating plasma TG clearance, PPARγ
agonists seem to lower plasma TG exclusively by enhancing plasma TG clearance [100, 108].The
stimulatory effect of PPARγ agonists on plasma TG clearance is
achieved by upregulating LPL expression and activity in adipose tissue [52, 100, 106, 109, 110], which is associated with an
increase in postheparin plasma LPL mass/total activity [101, 102]. As a consequence,
LPL-mediated lipolysis and the fractional clearance rate of VLDL-TG are
elevated [108]. Besides directly regulating
LPL production, PPARγ agonists may influence LPL-mediated
lipolysis by decreasing plasma levels of APOC3, a potent inhibitor of LPL [108].Interestingly,
in rats induction of LPL activity and gene expression by PPARγ
agonist was observed in inguinal but not retroperitoneal adipose tissue [111]. This type of adipose depot-specific
regulation of LPL by PPARγ likely accounts for the redistribution
of stored fat from visceral towards subcutaneous adipose tissue upon treatment
with PPARγ agonists [112]. Also, no induction of LPL
expression by PPARγ was observed in murine skeletal muscle [113].In
contrast to what is observed in vivo, PPARγ agonists decrease LPL activity in primary
rat and mouse 3T3 adipocytes [100, 114]. It can be hypothesized that
the inhibition of LPL activity may be mediated by upregulation of Angptl4,
similar to what was discussed for the suppression of LPL activity in various
cell types after treatment with PPARα agonist. In light of the recent finding
that rosiglitazone raises plasma Angptl4 levels in human subjects [115], and that Angptl4 increases
abundance of monomeric LPL in preheparin plasma (our unpublished data), it can
be speculated that upregulation of Angptl4 may also account for the observed
increase in plasma preheparin LPL levels in subjects treated with pioglitazone [108].Use
of gene targeting to study of the role of PPARγ in regulation of lipoprotein metabolism
has been complicated by the lethality of PPARγ null mice. However, mice with a
specific ablation of the PPARγ2 isoform are viable and, opposite to
the effect of PPARγ agonists, show elevated plasma TG
levels, especially on a leptin-deficient background [116]. A similar elevation of
plasma TG was observed in mice in which PPARγ was specifically deleted in adipose
tissue [117].Apart
from LPL, very few PPARγ target genes that impact on TG-rich
lipoproteins are known. It has been shown that LDL-receptor-related protein 1 (LRP-1),
which is involved in clearance of cholesteryl-esters from chylomicron remnants
and possibly HDL, is a direct target gene of PPARγ in human adipocytes [118]. These data suggest that upregulation
of LRP-1 may contribute to the stimulatory effect of PPARγ
agonists on clearance of TG-rich lipoproteins.


## 8. PPARγ and HDL Metabolism

Although PPARγ
agonists are best known for their ability to lower plasma glucose and TG
levels, depending on the type of PPARγ agonist and the type of animal
species/model, plasma levels of cholesterol and specific lipoprotein subclasses
may be altered as well [104, 119].   Recently, the results of two large clinical
trials involving either rosiglitazone or pioglitazone were reported. In the
ADOPT trial, 4360 subjects recently diagnosed with T2DM were randomly assigned
to treatment with metformin, glyburide, or rosiglitazone. After 4 years, plasma
HDLc levels were modestly higher in the rosiglitazone-treated patients [120].  In the proactive trial, 5238 patients with
type 2 diabetes received either pioglitazone or placebo. Again, a significant
increase in plasma HDLc levels was observed in the patients treated with
pioglitazone [121]. The small but reproducible increase
in plasma HDLc upon treatment with PPARγ agonists was substantiated in a
meta-analysis summarizing the effects of thiazolidinediones from a large number
of randomized controlled trails [122]. In addition, treatment with
PPARγ
agonists is associated with an increase in LDL size [101, 103, 119]. It has been reported that
the relative efficacy of pioglitazone towards ameliorating plasma lipid levels
is more favorable compared to rosiglitazone [119].Presently,
the mechanism(s) behind the HDLc raising effect of PPARγ
agonists remains elusive. Possibly, PPARγ agonists may carry minor agonist
activity towards PPARα. However, in contrast to PPARα
agonists, PPARγ agonists do not appear to have any
effect of APOA1 and APOA2 syntheses [100, 108]. The observation that plasma
HDLc levels do not respond to PPARγ agonist treatment in rodents
complicates study of the underlying mechanisms [100]. It is conceivable that the
modest increase in HDLc following PPARγ agonist treatment is due to reduced CETP-mediated exchange of VLDL TGs for HDL cholesterol, concomitant with a drop in
VLDL-TG levels. Finally, PPARγ
has been shown to upregulate expression of ABCA1 in macrophages [88, 123]. As ABCA1 is required for the flux of cholesterol from cells onto APOA1 to form nascent HDL, upregulation
of ABCA1 by PPARγ
may contribute to the HDLc-raising effect of PPARγ.
However, it still needs to be demonstrated that expression of ABCA1 is
under control of PPARγ in tissues responsible for the major
share of HDL synthesis, which are intestine and liver.


## 9. Conclusion

PPARs have a
major impact on levels of lipoproteins in plasma by governing the expression of
numerous genes involved in the synthesis, remodeling, and clearance of plasma
lipids and lipoproteins. The changes in plasma lipoprotein levels associated
with treatment with PPAR agonists, characterized by decreased plasma TG levels,
increased HDLc, and an increase in LDL size, are expected to decrease the risk
for cardiovascular disease. In recent years, several new proteins that play a
role in lipoprotein metabolism have been identified. In addition, the functional
characterization of other proteins involved in lipoprotein metabolism has
advanced significantly. As progress is made in PPAR-dependent gene
regulation, especially in human, our insight into the molecular mechanisms
underlying the effects of PPARs on plasma lipoproteins will further continue to  improve.



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