Published online before print March 14, 2002, doi: 10.1161/01.ATV.0000015598.86369.04
© 2002 American Heart Association, Inc.
Brief Reviews |
Pleiotropic Actions of Peroxisome Proliferator–Activated Receptors in Lipid Metabolism and Atherosclerosis
From UR545 INSERM, Département d’Athérosclérose, Institut Pasteur de Lille, and Faculté de Pharmacie, Université de Lille II, Lille, France.
Correspondence to Prof Bart Staels, U545 INSERM, Institut Pasteur de Lille, 1 rue Calmette, BP 245, 59019 Lille Cedex, France. E-mail bart.staels{at}pasteur-lille.fr
 |
Abstract |
|---|
 Top Abstract IntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
Peroxisome proliferator–activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPAR
mediates the hypolipidemic action of fibrates, PPAR
is the receptor for the antidiabetic glitazones. PPAR is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the ß-oxidative degradation of fatty acids. PPAR is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPARß/
is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPAR controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPAR and PPAR regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.
Key Words: nuclear receptors • HDL • inflammation • cholesterol • atherosclerosis
|
Introduction |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
The metabolic syndrome, which can be defined as the clustering of cardiovascular risk factors with insulin resistance, is characterized by the simultaneous presence of one or more of the following metabolic disorders: glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances, and hypertension. Peroxisome proliferator–activated receptors (PPARs) modulate these metabolic risk factors for cardiovascular disease associated with the metabolic syndrome. Whereas previous articles have summarized our present understanding of the role of PPARs in the control of glucose homeostasis, insulin resistance, and hypertension (see reviews1,2), the present review will focus on the plasma lipid–controlling actions of PPARs and their effects on atherogenesis.
|
Levels of Control of PPAR Activity |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
Fatty acids (FAs) and FA-derived compounds are natural ligands for PPAR
and PPAR. Natural eicosanoids derived from arachidonic acid via the lipoxygenase pathway, such as 8-S-hydroxytetraenoic acid and leukotriene B4, and oxidized phospholipids from oxidized lipoproteins activate PPAR.3 PPAR is a receptor for eicosanoid metabolites formed via the cyclooxygenase pathway, eg, prostaglandins, such as PGJ2, PGH1, and PGH2,4 and via the lipoxygenase pathway (15-hydroxytetraenoic acid).3 Similar to PPAR and PPAR, PPARß/ is a receptor for unsaturated FAs.
Synthetic agonists of PPARs are used in the treatment of metabolic diseases, such as dyslipidemia and type 2 diabetes. The antidiabetic glitazones, which are insulin sensitizers, are synthetic high-affinity ligands for PPAR.5 The hypolipidemic fibrate drugs are PPAR ligands.3 Recently, a series of subtype-specific high-affinity PPAR agonists have been synthesized. These include the human PPAR ligand GW7647,6 the PPAR activators GW1929 and GW7845,7,8 and the PPARß/-specific synthetic agonist GW501516.9
Upon ligand activation, PPAR, PPAR, and PPARß/ regulate transcription by dimerizing with the retinoid X receptor and binding to PPAR response elements (PPREs), within the regulatory regions of target genes (see review2). These PPREs usually consist of a direct repeat (DR1 or DR2) of the hexanucleotide AGGTCA sequence separated by 1 or 2 nucleotides.2
PPARs can also repress gene transcription in a DNA-binding–independent manner by interfering with the nuclear factor-
B, signal transducer(s) and activator(s) of transcription, activator protein-1, nuclear factor of activated T cells, CAAT box/enhancer binding protein, and Smad3 signaling pathways via protein-protein interactions and cofactor competition.10–13 Such trans-repression mechanism is likely to explain the anti-inflammatory actions of PPARs (see review10).
The PPAR transcriptional pathway is controlled by the following: the level of receptor expression and stability; its posttranslational modifications, ligand specificity, and availability; and cofactor recruitment (Figure 1).
|
Although PPAR is expressed preferentially in tissues in which FAs are catabolized, PPAR is present in adipose tissue, mammary glands, and numerous other tissues, and PPARß/ is ubiquitously expressed (see review2). The expression levels of PPARs are modulated by stimuli as varied as circadian rhythm,14 fasting,15,16 stress,14 and cold.17 Furthermore, various factors, such as corticosteroids,18,19 insulin,18,20 phorbol esters, and different cytokines,21 affect PPAR expression. Additionally, PPAR and retinoid X receptor ligands also modulate PPAR mRNA levels.22,23
PPAR protein levels are also subject to regulation. Although thiazolidinediones (TZDs) were shown to induce PPAR receptor ubiquitination and subsequent degradation by the proteasome,24 fibrates inhibit PPAR ubiquitination and increase PPAR protein half-life.25,26 PPAR and PPAR are phosphoproteins, and their phosphorylation status affects their transcriptional activity.27 For instance, Hansen et al28 reported that the cAMP signaling pathway, most likely via protein kinase A, increases PPARß/-mediated transactivation.
The ligand dependence of PPAR activity renders the availability of an activator an important regulator of receptor function. In that way, albumin, which sequesters PGJ2, controls the activity of PPAR.29 Similarly, ligand binding to FA-binding proteins (FABPs) has been proposed as a mechanism of intracellular transport of PPAR agonists from the cytoplasm to the nucleus, thus modulating the activation of the receptor.30
Upon binding, different ligands induce distinct conformations of the receptor, leading to differential coactivator recruitment (see review27) and, consequently, differential biological responses.31,32 These observations are at the basis of the "selective PPAR modulator" concept.33
|
PPARs and Dyslipidemia |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
The dyslipidemia associated with the metabolic syndrome is characterized by elevated plasma levels of triglycerides and small dense LDL particles and decreased HDL cholesterol. In vivo and in vitro data demonstrate that PPARs play a central role in the control of FA and lipoprotein metabolism.
Role of PPARs in Triglyceride and LDL Metabolism
In rodents, the central role of PPAR in FA metabolism under feeding/fasting conditions has been clearly demonstrated.15,16 On severe fasting, PPAR activity and expression are induced, allowing the catabolism of FAs to produce ketone bodies, which serve as energy sources for extrahepatic tissues. In humans, pharmacological PPAR activation with fibrates decreases plasma triglyceride concentrations by acting on different metabolic pathways.34 Fibrates increase FA uptake and catabolism, resulting (as a consequence) in limited triglyceride and VLDL production by the liver34 (Figure 2). Simultaneously, these hypolipidemic drugs enhance intravascular triglyceride metabolism.
|
The intracellular concentration of FAs is partly controlled by the regulation of their cellular uptake, which is mediated through different transporters, such as FA transport protein 1 (FATP1) and FA translocase (FAT/CD36). Fibrate treatment induces FATP1 and FAT mRNA levels in rodent liver, whereas glitazones induce the expression of these genes in white adipose tissue.35,36 In addition, the expression of the intracellular FABP, L-FABP, is regulated by fibrates in the liver.37 Interestingly, PPAR agonists failed to modulate L-FABP expression in the small intestine, whereas PPAR-null mice treated with a novel PPARß/-PPAR–specific agonist (GW2433) display an increase in L-FABP expression in this tissue,38 indicating that PPARß/ also regulates the expression of genes involved in FA metabolism. However, the physiological consequences of this regulation are presently unclear.
Intracellular FA flux is regulated by key proteins, ie, acyl coenzyme A synthetase (ACS), which catalyzes the esterification of FAs, thus favoring their cellular retention. By modulating the expression of ACS, PPAR and PPAR polarize FA fluxes.39
Furthermore, PPAR induces FA uptake and catabolism in mitochondria via stimulation of muscle and liver carnitine palmitoyltransferase I and II40–43 and several mitochondrial FA-catabolizing enzymes.44 When mitochondrial FA import is inhibited in male PPAR-null mice, massive cardiac and hepatic lipid accumulation and hypoglycemia are observed.45 This inhibition provokes a feedback upregulation of PPAR target genes in wild-type, but not in PPAR-null, mice.45
PPAR controls mitochondrial hydroxymethylglutaryl coenzyme A synthase expression and, thus, promotes ketone body synthesis.46,47 In rodent, but not in human, hepatocytes, PPAR induces the expression of various enzymes involved in peroxisomal ß-oxidation.34,47
Intravascular lipolysis activity is controlled by the activity of lipoprotein lipase (LPL). Fibrate-activated PPAR controls LPL activity by inducing its expression in the liver and by inhibiting the hepatic expression of apoC-III, an LPL activity and remnant catabolism inhibitor.48–50 These effects promote lipolysis and triglyceride-rich lipoprotein catabolism, thus decreasing the plasma levels of triglycerides. The role of PPAR on circulating VLDL levels is demonstrated in vivo in PPAR-null/apoE-null mice, which display higher VLDL production on high-fat diet feeding than do control mice.51
Glitazones also affect the circulating levels of free FAs, cholesterol, and triglycerides. In obese animal models, TZDs and non-TZD glitazones decrease the circulating levels of triglycerides by inducing lipolysis (via activation of LPL expression in adipocytes) and clearance of triglyceride-rich lipoproteins.52–54 In rodents, simultaneous administration of PPAR and PPAR activators results in a more efficient hypotriglyceridemic activity, which is likely due to combined actions on liver apoC-III and adipose tissue LPL expression.55 The induction of LPL by PPAR promotes FA delivery, whereas induction of FATP and ACS results in enhanced FA uptake. These actions contribute to enhanced triglyceride storage in adipose tissue. PPAR also modulates the expression of enzymes involved in the synthesis of FA and triglycerides, such as malic enzyme.56 Although the triglyceride-lowering activity of PPAR agonists in animal models is well documented, substantial controversy exists concerning their hypotriglyceridemic activity in humans.
PPARs, HDL Metabolism, and the Reverse Cholesterol Transport (RCT) Pathway
The RCT pathway mediates the centripetal transport of cholesterol from peripheral cells back to the liver. Cholesterol from peripheral cells is captured by HDL particles, which transport it back to the liver, where cholesterol is eliminated either directly into the bile or after metabolism in bile acids. PPARs influence the RCT pathway by regulating macrophage cholesterol efflux, HDL cholesterol transport in plasma, and bile acid synthesis (Figure 3).
|
Cholesterol efflux, the first step of the RCT, occurs either via passive diffusion or via transmembrane transporters, such as the scavenger receptor (SR) class B type 1 (SR-B1/CLA-1) and the ATP-binding cassette A1 (ABCA1) proteins. In human macrophages, PPAR and PPAR activators induce protein levels of SR-B1/CLA-1,57 whereas ligands of all 3 PPAR isotypes induce the expression of ABCA1.9,58,59 PPAR and PPAR induce ABCA1 by an indirect mechanism via induction of the nuclear liver X receptor (LXR).58,59 However, the molecular mechanism of ABCA1 induction by PPARß/ activators appears to be LXR independent.9 Increased ABCA1 expression results in a higher cholesterol efflux from macrophages. The major contribution of ABCA1 in the control of plasma HDL cholesterol levels has been highlighted by the identification of mutations in the ABCA1 gene in patients with familial HDL deficiency and Tangier disease.
ApoA-I and apoA-II are the major HDL apolipoproteins. In humans, PPAR increases the transcription of these 2 genes via binding to PPREs in their promoters,60,61 an effect that contributes to the increase of HDL concentrations following fibrate treatment. Although the increase of plasma apoA-I is undoubtedly beneficial, substantial controversy exists concerning the role of apoA-II in atherosclerosis. Indeed, whereas transgenic mice overexpressing murine apoA-II are more prone to develop atherosclerosis,62 overexpression of human apoA-II protects against atherogenesis.63 PPARß/-specific agonists also increase plasma HDL cholesterol concentrations in insulin-resistant mice and obese rhesus monkeys.9,64 The molecular mechanisms behind this increase remain to be clarified.
Recently, Bouly et al65 have shown that PPAR agonists induce the expression and activity of the phospholipid transfer protein (PLTP), an enzyme catalyzing the transfer of phospholipids from VLDL/LDL to HDL, in mice. PLTP induction contributes to the marked enlargement of HDL in fenofibrate-treated mice. Such action may also be antiatherogenic, since PLTP deficiency results in an enhanced susceptibility to atherosclerosis, which is due to decreased antioxidant transfer to endothelial cells.66 However, although fibrates influence the expression of HDL-remodeling enzymes, such as PLTP and lecithin-cholesterol acyltransferase, in rat liver,67 little is known about the regulation of these proteins in humans.
Cholesterol is excreted from the liver into the bile either directly or after conversion into bile acids. The role of PPAR in the control of bile acid synthesis and composition is still unclear and controversial. Whereas PPAR has been shown to induce the hepatic expression of LXR,68 which subsequently upregulates the expression of cholesterol 7-hydroxylase (CYP7A1),69 fibrates reduce the activity of this enzyme in rodents and humans.70–72 By contrast, PPAR has been reported as a positive regulator of murine and human CYP7A promoter activity.73 Thus, the role of PPAR in CYP7A expression and activity is not completely understood. However, activated PPAR induces the expression of cholesterol 12-hydroxylase (CYP8B1), an enzyme that determines the lithogenic index (ratio cholic acid versus chenodeoxycholic acid).74
|
PPARs and Atherogenesis |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
Atherosclerosis is a complex process characterized by lipid accumulation in the arterial wall. Atherogenesis starts with the attraction, recruitment, and activation of different cell types, including monocytes/macrophages, T lymphocytes, endothelial cells, and intimal smooth muscle cells (SMCs). This cellular activation provokes a local inflammatory response. As regulators of lipid and lipoprotein metabolism, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Clinical studies have shown that fibrates prevent atherosclerotic lesion progression.75–77 Although less data are available in humans with respect to glitazones, in rodents, the PPAR
ligand troglitazone inhibits SMC proliferation and decreases the intima and media thickness of carotid arteries.78 PPARs are expressed in most cell types of the vascular wall as well as in atherosclerotic lesions (see review10), where they affect atherogenic processes (Figure 4).
|
PPARs Modulate Early Stages of Atherogenesis
Figure 4 shows the modulation of atherogenesis and atherothrombosis by PPARs. PPARs regulate chemoattraction and cellular adhesion to endothelial cells (Figure 4). PPAR and PPAR activators repress thrombin-induced expression of endothelin-1, a potent vasoconstrictor peptide and inducer of SMC proliferation.79,80 Although the expression of monocyte chemoattractant protein (MCP)-1, a chemokine that promotes monocyte chemotaxis, is clearly inhibited by PPAR ligands, 81 the effect of PPAR activators is still unclear. In human aortic endothelial cells, natural and synthetic PPAR ligands stimulate the synthesis of MCP-1.82 In contrast, Pasceri et al83 have reported that fibrates reduce C-reactive protein (CRP)-induced expression of MCP-1 in human umbilical vein endothelial cells. PPAR activation blocks endothelial expression of interferon (IFN)-–inducible 10-kDa protein, a monokine induced by IFN-, and IFN-inducible T-cell -chemoattractant, which are chemokines that promote T-cell recruitment to sites of inflammation.84 Furthermore, PPARs modulate T-lymphocyte proliferation and immune activation.85,86
In monocytes, glitazones decrease the expression of CCR2, the transmembrane receptor for MCP-1.87 PPAR and PPAR activators reduce cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1.88,89 These adhesion molecules play a critical role in the recruitment of leukocytes and monocytes to atherosclerotic lesions. In vivo studies have demonstrated that troglitazone significantly reduces monocyte/macrophage recruitment to atherosclerotic lesions in apoE-null mice.90
PPARs Control Lipid Accumulation Within the Plaque
Although PPARs do not influence macrophage differentiation, they play an important role in regulating cholesterol homeostasis in macrophages (Figure 4). As described above, PPAR, PPAR, and PPARß/ activators induce the expression of ABCA1 and SR-BI, thus promoting cholesterol efflux from macrophages. By acting through posttranscriptional mechanisms,91,92 PPAR ligands decrease the protein level of SR-A, which is involved in the uptake of modified LDL. In addition, PPAR agonists induce the expression of CD36, a scavenger receptor for oxidized LDL in macrophages.91,92 The net effect is that neither PPAR nor PPAR promotes cholesterol accumulation in macrophages or foam cell formation.58,91 In contrast, activation of PPARß/, whose expression is increased during the differentiation of THP-1–derived human macrophages, increases the expression of genes involved in lipid uptake and storage, such as SR-A and CD36.93 These results identify PPARß/ as a potential promoter of macrophage lipid accumulation and suggest a role for PPARß/ in the pathology of atherosclerosis.
The atheroprotective role of PPAR has been further documented in animal models of atherosclerosis.7,94,95 In male LDL receptor–null mice, rosiglitazone and GW7845 treatment reduces the progression of atherosclerotic lesions and decreases macrophage accumulation in intimal xanthomas.7,94 Intriguingly, in these studies, female mice did not exhibit a reduction in atherosclerosis in response to PPAR ligand treatment.7 This lack of response could be partly explained by the decrease of HDL levels in female mice treated with PPAR ligands.7 Li et al7 related these differences to influences of estrogens and progestins, inasmuch as their preliminary studies indicate the metabolic response to rosiglitazone and GW7845 in ovariectomized female mice to be much more similar to that in male mice. In male and female apoE-null mice, troglitazone inhibits fatty steak formation while enhancing HDL cholesterol levels and increasing CD36 mRNA levels in the aorta.95 Surprisingly, PPAR-null/apoE-null mice develop less atherosclerotic lesions than do apoE-null control mice when they are fed a high-fat diet.51 Furthermore, these double PPAR/apoE-knockout mice display higher concentrations of atherogenic lipoproteins, but they also demonstrate higher insulin sensitivity and lower blood pressure.51 The lower blood pressure in PPAR-null animals might contribute to the reduced atherosclerotic lesions observed in these animals, despite the higher levels of atherogenic lipoproteins. In contrast, irradiated LDL receptor– null mice reconstituted with bone marrow from PPAR-null mice present more atherosclerotic lesions when compared with control mice, suggesting that macrophage PPAR expression inhibits early atherosclerotic lesion formation.96 Because PPAR-null macrophages and aortas present an enhanced production of tumor necrosis factor (TNF)- and interleukin (IL)-6, the inhibitory activity of PPAR on the formation of atherosclerotic lesions may be related to the control of cytokine production during vascular inflammation.96,97
PPARs and the Local Inflammatory Response
The activation of cells in atherosclerotic lesions leads to the release of proinflammatory molecules and the onset of a chronic inflammatory response (Figure 4). Various studies have demonstrated that PPARs inhibit the expression of inflammatory genes, such as cytokines, metalloproteases, and acute-phase reactants (see review98). PPARs exert anti-inflammatory activities in different immunological and vascular cell types, such as monocytes/macrophages, endothelial cells, SMCs, dendritic cells, and T lymphocytes.
Incubation of human monocytes with natural (PGJ2) and synthetic PPAR ligands inhibits the production of inflammatory cytokines, such as TNF-, IL-1ß, IL-6, IL-8, and IL-10.99,100 However, most pronounced effects are observed with PGJ2, which is not very selective for PPAR and also acts via PPAR-independent mechanisms.98 Furthermore, certain anti-inflammatory properties of PPAR agonists were observed in PPAR-null embryonic stem cell–derived macrophages, albeit at extremely high concentrations.92 Thus, glitazones and natural PPAR ligands appear to exert anti-inflammatory activities via PPAR-dependent and -independent mechanisms.
In human aortic SMCs, PPAR activators inhibit the expression of inducible cyclooxygenase-2 and IL-6.101 In human monocytes/macrophages, PPAR activators inhibit cytokine-induced expression of VCAM-1 and tissue factor (TF).88,102,103 In rat aortic SMCs, PGJ2 and 9-HODE induce the expression of type II–secreted phospholipase A2 (type II-sPLA2), an enzyme involved in the hydrolysis of phospholipids. Induced expression of type II-sPLA2 generates lipid inflammatory mediators, such as lysophosphatidic and arachidonic acids.104 Type II-sPLA2 increases lipoxygenase-mediated PPAR agonist (HODE) production from LDL105 and may initially lead to a PPAR-independent proinflammatory activity, followed by a PPAR-dependent arrest of the inflammatory response. Results from studies using PPAR-null mice clearly demonstrate a role for PPAR in the control of the inflammatory response.80,106
The anti-inflammatory activities of PPAR and PPAR activators have been evidenced in humans. In patients with mild hyperlipidemia, fenofibrate treatment has been shown to decrease the circulating levels of IL-6 and to lower the plasma levels of various risk factors for cardiovascular disease, such as fibrinogen and CRP, whose production is controlled by cytokines.83,101 Similarly, rosiglitazone treatment of patients with type 2 diabetes significantly reduces plasma levels of IL-6 and CRP.107
PPARs, Plaque Stability, and Atherothrombosis
Plaque rupture is the end stage of the atherogenic process, leading to thrombus formation, occlusion, and the clinical sequels of atherosclerosis (Figure 4). Plaque instability is partly due to the degradation of the extracellular matrix in the fibrous cap. PPAR activators inhibit the expression of metalloproteinase-9, a secreted matrix-degrading protein.108 This PPAR-dependent inhibition may prevent the rupture of the atherosclerotic plaque and subsequent thrombosis. On the other hand, troglitazone and PGJ2 inhibit the migration of SMCs, which occurs during atherosclerotic plaque formation. This effect may be due to the inhibition of secretion of metalloproteinases, which contribute to this process.109 Furthermore, glitazones inhibit vascular SMC (VSMC) expression of Ets-1, a transcription factor regulating matrix metalloproteinase gene transcription.110 This inhibition results in a decreased VSMC migration within the plaque.
In addition, PPARs also modulate platelet aggregation. PPAR activators inhibit the expression of thromboxane synthase by a mechanism involving protein-protein interaction between PPAR and the nuclear factor-E2–related factor 2.111 This results in a decreased production of thromboxane A2, a potent platelet aggregation inducer. Moreover, the expression of the thromboxane receptor is inhibited by PPAR activators in rat VSMCs.112 PPAR also inhibits the expression of the platelet-activating factor receptor and TF in human monocytes and macrophages.102,103,113 These actions may result in a decreased thrombogenic response.
Glitazones and fibrates also modulate the secretion of the thrombosis inducer plasminogen activator inhibitor type 1.114,115 However, the molecular data are still confusing,116,117 and the role of PPARs in the regulation of plasminogen activator inhibitor type 1 and its consequences for atherothrombosis remain to be clarified.
Apoptosis is a major event in the pathophysiology of atherothrombosis. However, the significance of apoptosis in this process is unclear (see review118). PPAR and PPAR control apoptosis via negative cross talk with the antiapoptotic nuclear factor-B pathway in macrophages.119 Furthermore, PPAR inhibits the mitogenic induction of the cyclin-dependent kinase inhibitor p21 by modulating the protein kinase C- pathway in VSMCs.120 In addition, PPAR stimulates the expression of PTEN, a tumor suppressor that modulates the inflammatory response and several cellular functions, including cell migration, survival, and proliferation.121 However, it remains to be determined whether apoptosis induction by PPARs also occurs in vivo and is of clinical importance.
|
PPAR Activators in Clinical Practice |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
A wealth of clinical studies have affirmed that fibrates improve the cardiovascular risk profile. Several angiographic intervention trials, including the Lipid Coronary Angiographic Trial (LOCAT), the Diabetes Atherosclerosis Intervention Study (DAIS), and the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), have demonstrated beneficial effects of fibrates on atherosclerotic lesion progression.75–77 Furthermore, secondary prevention trials, such as the Veterans Administration-HDL-Cholesterol Intervention Trial (VA-HIT)122 and the Helsinki Heart Study,123 have demonstrated a decreased incidence of cardiovascular events after fibrate treatment. In patients with type 2 diabetes, who are characterized by moderate hypertriglyceridemia and low HDL cholesterol concentrations, fibrates decrease the incidence of myocardial infarction, as observed in the St. Mary’s, Ealing, Northwick Park Diabetes (SENDCAP) study.124
Several studies have been performed testing the effects of glitazone treatment on glucose homeostasis in various diabetic and insulin-resistant patient populations.125,126 Glitazone therapy lowers fasting and postprandial glucose levels and improves insulin-stimulated glucose disposal. However, the effect of glitazone on the plasma lipid profile in humans is controversial, and intervention trials assessing the influence of these compounds on the incidence of cardiovascular disease are still lacking. Nevertheless, troglitazone treatment of patients with type 2 diabetes has clearly established this molecule to be a potent inhibitor of early atherosclerotic lesion progression.127 In patients with type 2 diabetes, pioglitazone and rosiglitazone appear to have distinct effects on the plasma levels of triglycerides and LDL. Although pioglitazone treatment lowers serum concentrations of LDL and triglycerides, rosiglitazone treatment does not appear to lower triglyceride or to increase the levels of LDL cholesterol.125,128 Although the mechanistic basis for these difference is unclear, one possible explanation may be that pioglitazone has, albeit limited, PPAR activity.129 Despite their atheroprotective properties, certain glitazones present a significant risk of hepatotoxicity and heart failure; thus, their clinical use should be carefully monitored.130 Troglitazone has been withdrawn worldwide because of its hepatotoxic effects. The risk of heart failure with glitazones, which is likely due to plasma volume expansion, is enhanced when they are used in combination therapy with insulin.130
Running trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and PROACTIVE trials, will provide additional evidence for possible clinical cardiovascular benefits of PPAR and PPAR agonists in the diabetic population.
|
Conclusions |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
The intimate and causative relationships between lipid metabolism and coronary heart disease have stimulated research involving the physiological functions of the lipid-activated transcription factors of the PPAR family. This research has resulted in the development and understanding of the action mechanism of drugs useful in the treatment of metabolic disorders predisposing to atherosclerosis. With the use of recently developed potent subtype-specific agonists, it has been demonstrated that all 3 PPARs control lipid metabolism; however, the precise role of PPARß/
remains to be clarified at the molecular and physiological levels. The next years will be exciting with the prospect of development of novel PPAR agonists, with, for instance, mixed PPAR and PPAR activity. Moreover, it is conceivable that future development of drugs exerting their activity via PPARs will focus not so much on the search of more potent activators but on selective receptor modulators in an attempt to separate desirable from unwanted side effects. Finally, ongoing clinical studies with specific PPAR-PPARß/-PPAR (co)activators should prove (or disprove) their potent activity in reducing coronary events and total mortality. |
Acknowledgments |
|---|
O. Barbier is holder of a post-doctoral fellowship from the Ligue National contre le Cancer. C. Blanquart and I. Pineda Torra are supported by a fellowship from the Région Nord-Pas-de-Calais and from the European community (ERBFMBICT983214), respectively.
Received January 10, 2002; accepted February 25, 2002.
|
References |
|---|
|
TopAbstractIntroductionLevels of Control of...PPARs and DyslipidemiaPPARs and AtherogenesisPPAR Activators in Clinical...ConclusionsReferences |
|---|
1. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem. 2001; 70: 341–367.[CrossRef][Medline] [Order article via Infotrieve]
2.
Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999; 20: 649–688.
3. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000; 43: 527–550.[CrossRef][Medline] [Order article via Infotrieve]
4. Ferry G, Bruneau V, Beauverger P, Goussard M, Rodriguez M, Lamamy V, Dromaint S, Canet E, Galizzi JP, Boutin JA. Binding of prostaglandins to human PPARgamma: tool assessment and new natural ligands. Eur J Pharmacol. 2001; 417: 77–89.[CrossRef][Medline] [Order article via Infotrieve]
5.
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995; 270: 12953–12956.
6. Brown PJ, Stuart LW, Hurley KP, Lewis MC, Winegar DA, Wilson JG, Wilkison WO, Ittoop OR, Willson TM. Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. Bioorg Med Chem. 2001; 11: 1225–1227.
7. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000; 106: 523–531.[Medline] [Order article via Infotrieve]
8. Brown KK, Henke BR, Blanchard SG, Cobb JE, Mook R, Kaldor I, Kliewer SA, Lehmann JM, Lenhard JM, Harrington WW, Novak PJ, Faison W, Binz JG, Hashim MA, Oliver WO, Brown HR, Parks DJ, Plunket KD, Tong WQ, Menius JA, Adkison K, Noble SA, Willson TM. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes. 1999; 48: 1415–1424.[Abstract]
9.
Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001; 98: 5306–5311.
10. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000; 49: 497–505.[CrossRef][Medline] [Order article via Infotrieve]
11.
Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L, Farrar WL. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists: PPARgamma co-association with transcription factor NFAT. J Biol Chem. 2000; 275: 4541–4544.
12.
Gervois P, Vu-Dac N, Kleemann R, Kockx M, Dubois G, Laine B, Kosykh V, Fruchart JC, Kooistra T, Staels B. Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. J Biol Chem. 2001; 276: 33471–33477.
13.
Fu M, Zhang J, Zhu X, Myles DE, Willson TM, Liu X, Chen YE. PPARgamma inhibits TGFbeta-induced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3. J Biol Chem. 2001; 276: 45888–45894.
14.
Lemberger T, Saladin R, Vazquez M, Assimacopoulos F, Staels B, Desvergne B, Wahli W, Auwerx J. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem. 1996; 271: 1764–1769.
15.
Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999; 96: 7473–7478.
16. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999; 103: 1489–1498.[Medline] [Order article via Infotrieve]
17.
Guardiola-Diaz HM, Rehnmark S, Usuda N, Albrektsen T, Feltkamp D, Gustafsson JA, Alexson SE. Rat peroxisome proliferator-activated receptors and brown adipose tissue function during cold acclimatization. J Biol Chem. 1999; 274: 23368–23377.
18. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 1997; 99: 2416–2422.[Medline] [Order article via Infotrieve]
19.
Lemberger T, Staels B, Saladin R, Desvergne B, Auwerx J, Wahli W. Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J Biol Chem. 1994; 269: 24527–24530.
20. Steineger HH, Sorensen HN, Tugwood JD, Skrede S, Spydevold O, Gautvik KM. Dexamethasone and insulin demonstrate marked and opposite regulation of the steady-state mRNA level of the peroxisomal proliferator-activated receptor (PPAR) in hepatic cells: hormonal modulation of fatty-acid-induced transcription. Eur J Biochem. 1994; 225: 967–974.[Medline] [Order article via Infotrieve]
21. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature. 1999; 400: 378–382.[CrossRef][Medline] [Order article via Infotrieve]
22. Pearson SL, Cawthorne MA, Clapham JC, Dunmore SJ, Holmes SD, Moore GB, Smith SA, Tadayyon M. The thiazolidinedione insulin sensitizer, BRL 49653, increases the expression of PPAR-gamma and aP2 in adipose tissue of high-fat-fed rats. Biochem Biophys Res Commun. 1996; 229: 752–757.[CrossRef][Medline] [Order article via Infotrieve]
23. Valmaseda A, Carmona MC, Barbera MJ, Vinas O, Mampel T, Iglesias R, Villarroya F, Giralt M. Opposite regulation of PPAR-alpha and -gamma gene expression by both their ligands and retinoic acid in brown adipocytes. Mol Cell Endocrinol. 1999; 154: 101–109.[CrossRef][Medline] [Order article via Infotrieve]
24.
Hauser S, Adelmant G, Sarraf P, Wright HM, Mueller E, Spiegelman BM. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J Biol Chem. 2000; 275: 18527–18533.
25. Hirotani M, Tsukamoto T, Bourdeaux J, Sadano H, Osumi T. Stabilization of peroxisome proliferator-activated receptor alpha by the ligand. Biochem Biophys Res Commun. 2001; 288: 106–110.[CrossRef][Medline] [Order article via Infotrieve]
26. Blanquart C, Barbier O, Fruchart JC, Staels B, Glineur C. Peroxisome proliferator-activated receptor alpha turnover by the ubiquitin-proteasome system controls the ligand-induced expression level of its target genes. J Biol Chem. In press.
27. Pineda Torra I, Chinetti G, Duval C, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice. Curr Opin Lipidol. 2001; 12: 245–254.[CrossRef][Medline] [Order article via Infotrieve]
28.
Hansen JB, Zhang H, Rasmussen TH, Petersen RK, Flindt EN, Kristiansen K. Peroxisome proliferator-activated receptor delta-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling. J Biol Chem. 2001; 276: 3175–3182.
29.
Person EC, Waite LL, Taylor RN, Scanlan TS. Albumin regulates induction of peroxisome proliferator-activated receptor-gamma (PPARgamma) by 15-deoxy-delta(12–14)-prostaglandin J(2) in vitro and may be an important regulator of PPARgamma function in vivo. Endocrinology. 2001; 142: 551–556.
30.
Wolfrum C, Borrmann CM, Borchers T, Spener F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha- and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci U S A. 2001; 98: 2323–2328.
31.
Mukherjee R, Hoener PA, Jow L, Bilakovics J, Klausing K, Mais DE, Faulkner A, Croston GE, Paterniti JR. A selective peroxisome proliferator-activated receptor-gamma (PPARgamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Mol Endocrinol. 2000; 14: 1425–1433.
32. Rocchi S, Picard F, Vamecq J, Gelman L, Potier N, Zeyer D, Dubuquoy L, Bac P, Champy MF, Plunket KD, Leesnitzer LM, Blanchard SG, Desreumaux P, Moras D, Renaud JP, Auwerx J. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol Cell. 2001; 8: 737–747.[CrossRef][Medline] [Order article via Infotrieve]
33. Olefsky JM. Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest. 2000; 106: 467–472.[Medline] [Order article via Infotrieve]
34.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998; 98: 2088–2093.
35.
Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998; 273: 16710–16714.
36.
Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J. Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem. 1997; 272: 28210–28217.
37. Issemann I, Prince R, Tugwood J, Green S. A role for fatty acids and liver fatty acid binding protein in peroxisome proliferation? Biochem Soc Trans. 1992; 20: 824–827.[Medline] [Order article via Infotrieve]
38. Poirier H, Niot I, Monnot MC, Braissant O, Meunier-Durmort C, Costet P, Pineau T, Wahli W, Willson TM, Besnard P. Differential involvement of peroxisome-proliferator-activated receptors alpha and delta in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine. Biochem J. 2001; 355: 481–488.[CrossRef][Medline] [Order article via Infotrieve]
39.
Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem. 1995; 270: 19269–19276.
40.
Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem. 2000; 275: 16638–16642.
41.
Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem. 1998; 273: 8560–8563.
42.
Brandt JM, Djouadi F, Kelly DP. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem. 1998; 273: 23786–23792.
43. Louet JF, Chatelain F, Decaux JF, Park EA, Kohl C, Pineau T, Girard J, Pegorier JP. Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway. Biochem J. 2001; 354: 189–197.[CrossRef][Medline] [Order article via Infotrieve]
44.
Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem. 1998; 273: 5678–5684.
45. Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, Kelly DP. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice. J Clin Invest. 1998; 102: 1083–1091.[Medline] [Order article via Infotrieve]
46.
Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem. 1994; 269: 18767–18772.
47.
Lawrence JW, Li Y, Chen S, DeLuca JG, Berger JP, Umbenhauer DR, Moller DE, Zhou G. Differential gene regulation in human vs rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR)alpha: PPARalpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expression. J Biol Chem. 2001; 276: 31521–31527.
48. Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J, Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase: a potential mechanism for the hypolipidemic action of fibrates. J Clin Invest. 1995; 95: 705–712.
49.
Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs: suppression of apolipoprotein C-III. J Biol Chem. 1995; 270: 13470–13475.
50. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996; 15: 5336–5348.[Medline] [Order article via Infotrieve]
51. Tordjman K, Bernal-Mizrachi C, Zemany L, Weng S, Feng C, Zhang F, Leone TC, Coleman T, Kelly DP, Semenkovich CF. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J Clin Invest. 2001; 107: 1025–1034.[Medline] [Order article via Infotrieve]
52.
Way JM, Harrington WW, Brown KK, Gottschalk WK, Sundseth SS, Mansfield TA, Ramachandran RK, Willson TM, Kliewer SA. Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. Endocrinology. 2001; 142: 1269–1277.
53. Stevenson RW, Hutson NJ, Krupp MN, Volkmann RA, Holland GF, Eggler JF, Clark DA, McPherson RK, Hall KL, Danbury BH, et al. Actions of novel antidiabetic agent englitazone in hyperglycemic hyperinsulinemic ob/ob mice. Diabetes. 1990; 39: 1218–1227.[Abstract]
54. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Meglasson MD. Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys. Diabetes. 1994; 43: 204–211.[Abstract]
55.
Lefebvre AM, Peinado-Onsurbe J, Leitersdorf I, Briggs MR, Paterniti JR, Fruchart JC, Fievet C, Auwerx J, Staels B. Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates. Arterioscler Thromb Vasc Biol. 1997; 17: 1756–1764.
56.
Castelein H, Gulick T, Declercq PE, Mannaerts GP, Moore DD, Baes MI. The peroxisome proliferator activated receptor regulates malic enzyme gene expression. J Biol Chem. 1994; 269: 26754–26758.
57.
Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation. 2000; 101: 2411–2417.
58. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med. 2001; 7: 53–58.[CrossRef][Medline] [Order article via Infotrieve]
59. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001; 7: 161–171.[CrossRef][Medline] [Order article via Infotrieve]
60.
Vu-Dac N, Schoonjans K, Laine B, Fruchart JC, Auwerx J, Staels B. Negative regulation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element. J Biol Chem. 1994; 269: 31012–31018.
61. Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J, Fruchart JC, Staels B, Auwerx J. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest. 1995; 96: 741–750.
62.
Warden CH, Hedrick CC, Qiao JH, Castellani LW, Lusis AJ. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science. 1993; 261: 469–472.
63.
Tailleux A, Bouly M, Luc G, Castro G, Caillaud JM, Hennuyer N, Poulain P, Fruchart JC, Duverger N, Fievet C. Decreased susceptibility to diet-induced atherosclerosis in human apolipoprotein A-II transgenic mice. Arterioscler Thromb Vasc Biol. 2000; 20: 2453–2458.
64. Leibowitz MD, Fievet C, Hennuyer N, Peinado-Onsurbe J, Duez H, Bergera J, Cullinan CA, Sparrow CP, Baffic J, Berger GD, Santini C, Marquis RW, Tolman RL, Smith RG, Moller DE, Auwerx J. Activation of PPARdelta alters lipid metabolism in db/db mice. FEBS Lett. 2000; 473: 333–336.[CrossRef][Medline] [Order article via Infotrieve]
65.
Bouly M, Masson D, Gross B, Jiang XC, Fievet C, Castro G, Tall AR, Fruchart JC, Staels B, Lagrost L, Luc G. Induction of the phospholipid transfer protein gene accounts for the high density lipoprotein enlargement in mice treated with fenofibrate. J Biol Chem. 2001; 276: 25841–25847.
66. Jiang XC, Qin S, Lin M, Schneider M, Tall AR, Lagrost L. Phospholipid transfer protein (PLTP) deficiency represents an anti-oxidant state in mice. Circulation. 2001; 104: 1118.Abstract.
67. Staels B, Van Tol A, Skretting G, Auwerx J. Lecithin: cholesterol acyltransferase gene expression is regulated in a tissue-selective manner by fibrates. J Lipid Res. 1992; 33: 727–735.[Abstract]
68.
Tobin KA, Steineger HH, Alberti S, Spydevold O, Auwerx J, Gustafsson JA, Nebb HI. Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Mol Endocrinol. 2000; 14: 741–752.
69. Chiang JY, Kimmel R, Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene. 2001; 262: 257–265.[CrossRef][Medline] [Order article via Infotrieve]
70. Stahlberg D, Reihner E, Rudling M, Berglund L, Einarsson K, Angelin B. Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: reduced activity of cholesterol 7 alpha-hydroxylase. Hepatology. 1995; 21: 1025–1030.[CrossRef][Medline] [Order article via Infotrieve]
71.
Bertolotti M, Concari M, Loria P, Abate N, Pinetti A, Guicciardi ME, Carulli N. Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation in humans. Arterioscler Thromb Vasc Biol. 1995; 15: 1064–1069.
72.
Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol. 2001; 21: 1840–1845.
73.
Cheema SK, Agellon LB. The murine and human cholesterol 7alpha-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor alpha. J Biol Chem. 2000; 275: 12530–12536.
74.
Hunt MC, Yang YZ, Eggertsen G, Carneheim CM, Gafvels M, Einarsson C, Alexson SE. The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis. J Biol Chem. 2000; 275: 28947–28953.
75. DAIS: effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357: 905–910.[CrossRef][Medline] [Order article via Infotrieve]
76. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347: 849–853.[CrossRef][Medline] [Order article via Infotrieve]
77.
Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol: Lipid Coronary Angiography Trial (LOCAT) Study Group. Circulation. 1997; 96: 2137–2143.
78. Law RE, Meehan WP, Xi XP, Graf K, Wuthrich DA, Coats W, Faxon D, Hsueh WA. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest. 1996; 98: 1897–1905.[Medline] [Order article via Infotrieve]
79. Satoh H, Tsukamoto K, Hashimoto Y, Hashimoto N, Togo M, Hara M, Maekawa H, Isoo N, Kimura S, Watanabe T. Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function. Biochem Biophys Res Commun. 1999; 254: 757–763.[CrossRef][Medline] [Order article via Infotrieve]
80.
Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P, Staels B. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res. 1999; 85: 394–402.
81. Murao K, Imachi H, Momoi A, Sayo Y, Hosokawa H, Sato M, Ishida T, Takahara J. Thiazolidinedione inhibits the production of monocyte chemoattractant protein-1 in cytokine-treated human vascular endothelial cells. FEBS Lett. 1999; 454: 27–30.[CrossRef][Medline] [Order article via Infotrieve]
82.
Lee H, Shi W, Tontonoz P, Wang S, Subbanagounder G, Hedrick CC, Hama S, Borromeo C, Evans RM, Berliner JA, Nagy L. Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ Res. 2000; 87: 516–521.
83.
Pasceri V, Chang J, Willerson JT, Yeh ET. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103: 2531–2534.
84.
Marx N, Mach F, Sauty A, Leung JH, Sarafi MN, Ransohoff RM, Libby P, Plutzky J, Luster AD. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000; 164: 6503–6508.
85.
Jones DC, Ding X, Daynes RA. Nuclear receptor PPARalpha is expressed in resting murine lymphocytes: the PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. J Biol Chem. 2002; 277: 6838–6845.
86. Wang P, Anderson PO, Chen S, Paulsson KM, Sjogren HO, Li S. Inhibition of the transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferator-activated receptor gamma ligands. Int Immunopharmacol. 2001; 1: 803–812.[CrossRef][Medline] [Order article via Infotrieve]
87. Han KH, Quehenberger O. Ligands for peroxisome proliferator-activated receptor inhibit monocyte CCR2 expression stimulated by plasma lipoproteins. Trends Cardiovasc Med. 2000; 10: 209–216.[CrossRef][Medline] [Order article via Infotrieve]
88.
Marx N, Sukhova GK, Collins T, Libby P, Plutzky J, PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999; 99: 3125–3131.
89.
Jackson SM, Parhami F, Xi XP, Berliner JA, Hsueh WA, Law RE, Demer LL. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol. 1999; 19: 2094–2104.
90.
Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000; 101: 235–238.
91. Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS, Mortensen RM, Spiegelman BM, Freeman MW. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med. 2001; 7: 41–47.[CrossRef][Medline] [Order article via Infotrieve]
92. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001; 7: 48–52.[CrossRef][Medline] [Order article via Infotrieve]
93.
Vosper H, Patel L, Graham TL, Khoudoli GA, Hill A, MacPhee CH, Pinto I, Smith SA, Suckling KE, Wolf CR, Palmer CN. The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. J Biol Chem. 2001; 276: 44258–44265.
94.
Collins AR, Meehan WP, Kintscher U, Jackson S, Wakino S, Noh G, Palinski W, Hsueh WA, Law RE. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor–deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 365–371.
95.
Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol. 2001; 21: 372–377.
96. Babaev VR, Major AS, Zhu T, Hiroyuki I, Dove DE, Fazio S, Linto MF, Semenkovich CF. Macrophage expression of PPAR-alpha inhibits atherosclerotic lesion formation in LDL-receptor deficient mice. Circulation. 2001; 104: 45–46.Abstract.
97.
Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem. 1999; 274: 32048–32054.
98. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001; 169: 453–459.[Abstract]
99. Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol. 1999; 66: 733–739.[Abstract]
100. Azuma Y, Shinohara M, Wang PL, Ohura K. 15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-10 and IL-12 production by macrophages. Biochem Biophys Res Commun. 2001; 283: 344–346.[CrossRef][Medline] [Order article via Infotrieve]
101. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998; 393: 790–793.[CrossRef][Medline] [Order article via Infotrieve]
102.
Neve BP, Corseaux D, Chinetti G, Zawadzki C, Fruchart JC, Duriez P, Staels B, Jude B. PPARalpha agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation. 2001; 103: 207–212.
103.
Marx N, Mackman N, Schonbeck U, Yilmaz N, Hombach VV, Libby P, Plutzky J. PPARalpha activators inhibit tissue factor expression and activity in human monocytes. Circulation. 2001; 103: 213–219.
104.
Couturier C, Brouillet A, Couriaud C, Koumanov K, Bereziat G, Andreani M. Interleukin 1beta induces type II-secreted phospholipase A(2) gene in vascular smooth muscle cells by a nuclear factor kappaB and peroxisome proliferator-activated receptor-mediated process. J Biol Chem. 1999; 274: 23085–23093.
105. Neuzil J, Upston JM, Witting PK, Scott KF, Stocker R. Secretory phospholipase A2 and lipoprotein lipase enhance 15-lipoxygenase-induced enzymic and nonenzymic lipid peroxidation in low-density lipoproteins. Biochemistry. 1998; 37: 9203–9210.[CrossRef][Medline] [Order article via Infotrieve]
106. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996; 384: 39–43.[CrossRef][Medline] [Order article via Infotrieve]
107. Fuell DL, Freed MI, Greenberg AS, Haffner S, Chen H. The effect of treatment with rosiglitazone on C-reactive protein and interleukin-6 in patients with type 2 diabetes. Diabetes. 2001; 50: A435.Abstract.
108.
Marx N, Sukhova G, Murphy C, Libby P, Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma (PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol. 1998; 153: 17–23.
109.
Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. Circ Res. 1994; 75: 41–54.
110. Goetze S, Kintscher U, Kim S, Meehan WP, Kaneshiro K, Collins AR, Fleck E, Hsueh WA, Law RE. Peroxisome proliferator-activated receptor-gamma ligands inhibit nuclear but not cytosolic extracellular signal-regulated kinase/mitogen-activated protein kinase-regulated steps in vascular smooth muscle cell migration. J Cardiovasc Pharmacol. 2001; 38: 909–921.[CrossRef][Medline] [Order article via Infotrieve]
111.
Ikeda Y, Sugawara A, Taniyama Y, Uruno A, Igarashi K, Arima S, Ito S, Takeuchi K. Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2. J Biol Chem. 2000; 275: 33142–33150.
112. Sugawara A, Takeuchi K, Uruno A, Ikeda Y, Arima S, Sato K, Kudo M, Taniyama Y, Ito S. Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes. Hypertens Res. 2001; 24: 229–233.[CrossRef][Medline] [Order article via Infotrieve]
113. Hourton D, Delerive P, Stankova J, Staels B, Chapman MJ, Ninio E. Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor alpha down-regulate platelet-activating-factor receptor expression in human macrophages. Biochem J. 2001; 354: 225–232.[CrossRef][Medline] [Order article via Infotrieve]
114. Durrington PN, Mackness MI, Bhatnagar D, Julier K, Prais H, Arrol S, Morgan J, Wood GN. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis. 1998; 138: 217–225.[CrossRef][Medline] [Order article via Infotrieve]
115. Kato K, Yamada D, Midorikawa S, Sato W, Watanabe T. Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. Metabolism. 2000; 49: 662–665.[CrossRef][Medline] [Order article via Infotrieve]
116. Kato K, Satoh H, Endo Y, Yamada D, Midorikawa S, Sato W, Mizuno K, Fujita T, Tsukamoto K, Watanabe T. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPARgamma in endothelial function. Biochem Biophys Res Commun. 1999; 258: 431–435.[CrossRef][Medline] [Order article via Infotrieve]
117.
Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol. 1999; 19: 546–551.
118. Martinet W, Kockx MM. Apoptosis in atherosclerosis: focus on oxidized lipids and inflammation. Curr Opin Lipidol. 2001; 12: 535–541.[CrossRef][Medline] [Order article via Infotrieve]
119.
Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998; 273: 25573–25580.
120.
Wakino S, Kintscher U, Liu Z, Kim S, Yin F, Ohba M, Kuroki T, Schonthal AH, Hsueh WA, Law RE. PPARgamma ligands inhibit mitogenic induction of p21Cip1 by modulating the PKC pathway in vascular smooth muscle cells. J Biol Chem. 2001; 276: 47650–47657.
121. Patel L, Pass I, Coxon P, Downes CP, Smith SA, MacPhee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol. 2001; 11: 764–768.[CrossRef][Medline] [Order article via Infotrieve]
122.
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999; 341: 410–418.
123. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study. primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317: 1237–1245.[Abstract]
124. Elkeles RS, Diamond JR, Poulter C, Dhanjil S, Nicolaides AN, Mahmood S, Richmond W, Mather H, Sharp P, Feher MD. Cardiovascular outcomes in type 2 diabetes: a double-blind placebo-controlled study of bezafibrate: the St. Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care. 1998; 21: 641–648.[Abstract]
125. Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med. 2001; 111: 10–17.[Medline] [Order article via Infotrieve]
126. Kaplan F, Al-Majali K, Betteridge DJ. PPARS, insulin resistance and type 2 diabetes. J Cardiovasc Risk. 2001; 8: 211–217.[CrossRef][Medline] [Order article via Infotrieve]
127.
Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 1998; 83: 1818–1820.
128. Gegick CG, Altheimer MD. Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice. Endocr Pract. 2001; 7: 162–169.[Medline] [Order article via Infotrieve]
129. Smith U, Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001; 121: 13–18.
130. Gale EA. Lessons from the glitazones: a story of drug development. Lancet. 2001; 357: 1870–1875.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Miller Dyslipidemia and cardiovascular risk: the importance of early prevention QJM, September 1, 2009; 102(9): 657 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Bonsignore and J. Eckel Metabolic aspects of obstructive sleep apnoea syndrome Eur. Respir. Rev., June 1, 2009; 18(112): 113 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Kim, H. Moradi, J. Yuan, K. Norris, and N. D. Vaziri Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1297 - F1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-S. Lee, Y.-W. Kwon, H.-M. Yang, S.-H. Kim, T.-Y. Kim, J. Hur, K.-W. Park, H.-J. Cho, H.-J. Kang, Y.-B. Park, et al. New Mechanism of Rosiglitazone to Reduce Neointimal Hyperplasia: Activation of Glycogen Synthase Kinase-3{beta} Followed by Inhibition of MMP-9 Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 472 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Biscetti and R. Pola Endothelial Progenitor Cells and Angiogenesis Join the PPARty Circ. Res., July 3, 2008; 103(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Pedro-Botet Review: The role of fenofibrate in reducing cardiovascular risk in type 2 diabetes The British Journal of Diabetes & Vascular Disease, January 1, 2008; 8(1): 22 - 27. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Steiner Atherosclerosis in type 2 diabetes: a role for fibrate therapy? Diabetes and Vascular Disease Research, December 1, 2007; 4(4): 368 - 374. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure Stroke, November 1, 2007; 38(11): 3016 - 3022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. R. Babaev, H. Ishiguro, L. Ding, P. G. Yancey, D. E. Dove, W. J. Kovacs, C. F. Semenkovich, S. Fazio, and M. F. Linton Macrophage Expression of Peroxisome Proliferator Activated Receptor-{alpha} Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Deficient Mice Circulation, September 18, 2007; 116(12): 1404 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P.E. Kadoglou, F. Iliadis, C. D. Liapis, D. Perrea, N. Angelopoulou, and M. Alevizos Beneficial Effects of Combined Treatment With Rosiglitazone and Exercise on Cardiovascular Risk Factors in Patients With Type 2 Diabetes Diabetes Care, September 1, 2007; 30(9): 2242 - 2244. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Dongol, Y. Shah, I. Kim, F. J. Gonzalez, and M. C. Hunt The acyl-CoA thioesterase I is regulated by PPAR{alpha} and HNF4{alpha} via a distal response element in the promoter J. Lipid Res., August 1, 2007; 48(8): 1781 - 1791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Cha, X. Zhang, Y. Zhang, J. Wu, D. Su, J. Y. Han, X. Fang, B. Yu, M. D. Breyer, and Y. Guan Peroxisome Proliferator Activated Receptor {alpha}/{gamma} Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice Diabetes, August 1, 2007; 56(8): 2036 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Dunn, S. S. Ousman, R. A. Sobel, L. Zuniga, S. E. Baranzini, S. Youssef, A. Crowell, J. Loh, J. Oksenberg, and L. Steinman Peroxisome proliferator-activated receptor (PPAR){alpha} expression in T cells mediates gender differences in development of T cell-mediated autoimmunity J. Exp. Med., February 19, 2007; 204(2): 321 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Marcil, E. Delvin, A. T. Sane, A. Tremblay, and E. Levy Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette A1 and nuclear factors Cardiovasc Res, December 1, 2006; 72(3): 473 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M J. Chapman The effects of fibrates on lipid metabolism and inflammation in type 2 diabetes Diabetes and Vascular Disease Research, September 1, 2006; 3(1_suppl): S6 - S9. [Abstract] [PDF]
|
|
|
|
 |
|
 L Wei, M J Murphy, and T M MacDonald Impact on cardiovascular events of increasing high density lipoprotein cholesterol with and without lipid lowering drugs Heart, June 1, 2006; 92(6): 746 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zambon, P. Gervois, P. Pauletto, J.-C. Fruchart, and B. Staels Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR-{alpha} Activators: Clinical and Experimental Evidence Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 977 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marfella, M. D'Amico, K. Esposito, A. Baldi, C. Di Filippo, M. Siniscalchi, F. C. Sasso, M. Portoghese, F. Cirillo, F. Cacciapuoti, et al. The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Rosiglitazone Treatment Diabetes, March 1, 2006; 55(3): 622 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gomez-Garre, M. Herraiz, M. L. Gonzalez-Rubio, R. Bernal, P. Aragoncillo, A. Carbonell, J. J. Rufilanchas, and A. Fernandez-Cruz Activation of peroxisome proliferator-activated receptor-{alpha} and -{gamma} in auricular tissue from heart failure patients Eur J Heart Fail, March 1, 2006; 8(2): 154 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. F. Samaha, P. O. Szapary, N. Iqbal, M. M. Williams, L. T. Bloedon, A. Kochar, M. L. Wolfe, and D. J. Rader Effects of Rosiglitazone on Lipids, Adipokines, and Inflammatory Markers in Nondiabetic Patients With Low High-Density Lipoprotein Cholesterol and Metabolic Syndrome Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 624 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Campia, L. A. Matuskey, and J. A. Panza Peroxisome Proliferator-Activated Receptor-{gamma} Activation With Pioglitazone Improves Endothelium-Dependent Dilation in Nondiabetic Patients With Major Cardiovascular Risk Factors Circulation, February 14, 2006; 113(6): 867 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M J. Chapman Review: Fibrates: therapeutic review The British Journal of Diabetes & Vascular Disease, January 1, 2006; 6(1): 11 - 19. [Abstract] [PDF]
|
|
|
|
 |
|
 S Soumian, R Gibbs, A Davies, and C Albrecht mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease J. Clin. Pathol., December 1, 2005; 58(12): 1255 - 1260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Han, M. J. Quon, and K. K. Koh Beneficial Vascular and Metabolic Effects of Peroxisome Proliferator-Activated Receptor-{alpha} Activators Hypertension, November 1, 2005; 46(5): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, S. H. Han, M. J. Quon, J. Yeal Ahn, and E. K. Shin Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia Diabetes Care, June 1, 2005; 28(6): 1419 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Djouadi, F. Aubey, D. Schlemmer, and J. Bastin Peroxisome Proliferator Activated Receptor {delta} (PPAR{delta}) Agonist But Not PPAR{alpha} Corrects Carnitine Palmitoyl Transferase 2 Deficiency in Human Muscle Cells J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1791 - 1797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Stauber, H. Brown-Borg, J. Liu, M. P. Waalkes, A. Laughter, R. A. Staben, J. C. Coley, C. Swanson, K. A. Voss, J. J. Kopchick, et al. Constitutive Expression of Peroxisome Proliferator-Activated Receptor {alpha}-Regulated Genes in Dwarf Mice Mol. Pharmacol., March 1, 2005; 67(3): 681 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, K. Chen, N. Sinha, X. Zhang, Y. Wang, A. K. Sinha, F. Romeo, and J. L. Mehta The effects of PPAR-{gamma} ligand pioglitazone on platelet aggregation and arterial thrombus formation Cardiovasc Res, March 1, 2005; 65(4): 907 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Verreth, D. De Keyzer, M. Pelat, P. Verhamme, J. Ganame, J. K. Bielicki, A. Mertens, R. Quarck, N. Benhabiles, G. Marguerie, et al. Weight Loss-Associated Induction of Peroxisome Proliferator-Activated Receptor-{alpha} and Peroxisome Proliferator-Activated Receptor-{gamma} Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice Circulation, November 16, 2004; 110(20): 3259 - 3269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Rival, A. Stennevin, L. Puech, A. Rouquette, C. Cathala, F. Lestienne, E. Dupont-Passelaigue, J.-F. Patoiseau, T. Wurch, and D. Junquero Human Adipocyte Fatty Acid-Binding Protein (aP2) Gene Promoter-Driven Reporter Assay Discriminates Nonlipogenic Peroxisome Proliferator-Activated Receptor {gamma} Ligands J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 467 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Llaverias, M. Vazquez-Carrera, R. M. Sanchez, V. Noe, C. J. Ciudad, J. C. Laguna, and M. Alegret Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism J. Lipid Res., November 1, 2004; 45(11): 2015 - 2024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sung, S. Park, B. P. Yu, and H. Y. Chung Modulation of PPAR in Aging, Inflammation, and Calorie Restriction J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2004; 59(10): B997 - B1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yki-Jarvinen Thiazolidinediones N. Engl. J. Med., September 9, 2004; 351(11): 1106 - 1118. [Full Text] [PDF]
|
|
|
|
|
|
G.T. Chew and G.F. Watts Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the 'recoupling hypothesis' QJM, August 1, 2004; 97(8): 537 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Blanquart, R. Mansouri, R. Paumelle, J.-C. Fruchart, B. Staels, and C. Glineur The Protein Kinase C Signaling Pathway Regulates a Molecular Switch between Transactivation and Transrepression Activity of the Peroxisome Proliferator-Activated Receptor {alpha} Mol. Endocrinol., August 1, 2004; 18(8): 1906 - 1918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fu, D. Mukhopadhyay, N. O. Davidson, and J. Borensztajn The Peroxisome Proliferator-activated Receptor {alpha} (PPAR{alpha}) Agonist Ciprofibrate Inhibits Apolipoprotein B mRNA Editing in Low Density Lipoprotein Receptor-deficient Mice: EFFECTS ON PLASMA LIPOPROTEINS AND THE DEVELOPMENT OF ATHEROSCLEROTIC LESIONS J. Biol. Chem., July 2, 2004; 279(27): 28662 - 28669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kuwabara, K. Murakami, M. Todo, T. Aoki, T. Asaki, M. Murai, and J. Yano A Novel Selective Peroxisome Proliferator-Activated Receptor {alpha} Agonist, 2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipoprotein Profiles in KK-Ay Mice J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 970 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q H Khan, D E Pontefract, S Iyengar, and S Ye Evidence of differing genotypic effects of PPAR{alpha} in women and men J. Med. Genet., June 1, 2004; 41(6): e79 - e79. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Sidhu, Z. Kaposzta, H. S. Markus, and J. C. Kaski Effect of Rosiglitazone on Common Carotid Intima-Media Thickness Progression in Coronary Artery Disease Patients Without Diabetes Mellitus Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 930 - 934. [Abstract] [Full Text]
|
|
|
|
|
|
G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]
|
|
|
|
|
|
A. Zanchi, A. Chiolero, M. Maillard, J. Nussberger, H.-R. Brunner, and M. Burnier Effects of the Peroxisomal Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone on Renal and Hormonal Responses to Salt in Healthy Men J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1140 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Mehrabi, P. Haslmayer, S. Humpeler, G. Strauss-Blasche, W. Marktl, F. Tamaddon, N. Serbecic, G. Wieselthaler, T. Thalhammer, H. D. Glogar, et al. Quantitative analysis of peroxisome proliferator-activated receptor gamma (PPAR{gamma}) expression in arteries and hearts of patients with ischaemic or dilated cardiomyopathy Eur J Heart Fail, December 1, 2003; 5(6): 733 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Ceaser, A. Ramachandran, A.-L. Levonen, and V. M. Darley-Usmar Oxidized low-density lipoprotein and 15-deoxy-{Delta}12,14-PGJ2 increase mitochondrial complex I activity in endothelial cells Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2298 - H2308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Meerarani, G. Reiterer, M. Toborek, and B. Hennig Zinc Modulates PPAR{gamma} Signaling and Activation of Porcine Endothelial Cells J. Nutr., October 1, 2003; 133(10): 3058 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fontaine, G. Dubois, Y. Duguay, T. Helledie, N. Vu-Dac, P. Gervois, F. Soncin, S. Mandrup, J.-C. Fruchart, J. Fruchart-Najib, et al. The Orphan Nuclear Receptor Rev-Erb{alpha} Is a Peroxisome Proliferator-activated Receptor (PPAR) {gamma} Target Gene and Promotes PPAR{gamma}-induced Adipocyte Differentiation J. Biol. Chem., September 26, 2003; 278(39): 37672 - 37680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Satoh, Y. Ogawa, T. Usui, T. Tagami, S. Kono, H. Uesugi, H. Sugiyama, A. Sugawara, K. Yamada, A. Shimatsu, et al. Antiatherogenic Effect of Pioglitazone in Type 2 Diabetic Patients Irrespective of the Responsiveness to Its Antidiabetic Effect Diabetes Care, September 1, 2003; 26(9): 2493 - 2499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Barbier, D. Duran-Sandoval, I. Pineda-Torra, V. Kosykh, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-activated Receptor {alpha} Induces Hepatic Expression of the Human Bile Acid Glucuronidating UDP-glucuronosyltransferase 2B4 Enzyme J. Biol. Chem., August 29, 2003; 278(35): 32852 - 32860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Prieur, H. Coste, and J. C. Rodriguez The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-{alpha} and Contains a Novel Farnesoid X-activated Receptor Response Element J. Biol. Chem., July 3, 2003; 278(28): 25468 - 25480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kreisberg and A. Oberman Medical Management of Hyperlipidemia/Dyslipidemia J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2445 - 2461. [Full Text] [PDF]
|
|
|
|
|
|
G. Haraguchi, Y. Kobayashi, M. L. Brown, A. Tanaka, M. Isobe, S. H. Gianturco, and W. A. Bradley PPAR{alpha} and PPAR{gamma} activators suppress the monocyte-macrophage apoB-48 receptor J. Lipid Res., June 1, 2003; 44(6): 1224 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Barbier, L. Villeneuve, V. Bocher, C. Fontaine, I. P. Torra, C. Duhem, V. Kosykh, J.-C. Fruchart, C. Guillemette, and B. Staels The UDP-glucuronosyltransferase 1A9 Enzyme Is a Peroxisome Proliferator-activated Receptor alpha and gamma Target Gene J. Biol. Chem., April 11, 2003; 278(16): 13975 - 13983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vakkilainen, G. Steiner, J.-C. Ansquer, F. Aubin, S. Rattier, C. Foucher, A. Hamsten, M.-R. Taskinen, and on behalf of the DAIS Group Relationships Between Low-Density Lipoprotein Particle Size, Plasma Lipoproteins, and Progression of Coronary Artery Disease: The Diabetes Atherosclerosis Intervention Study (DAIS) Circulation, April 8, 2003; 107(13): 1733 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Wang, R. D. Weisel, P. P. Liu, P. W.M. Fedak, and S. Verma Glitazones and Heart Failure: Critical Appraisal for the Clinician Circulation, March 18, 2003; 107(10): 1350 - 1354. [Full Text] [PDF]
|
|
|
|
|
|
G. Charriere, B. Cousin, E. Arnaud, M. Andre, F. Bacou, L. Penicaud, and L. Casteilla Preadipocyte Conversion to Macrophage. EVIDENCE OF PLASTICITY J. Biol. Chem., March 7, 2003; 278(11): 9850 - 9855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.A. Argmann, C.G. Sawyez, C.J. McNeil, R.A. Hegele, and M.W. Huff Activation of Peroxisome Proliferator-Activated Receptor Gamma and Retinoid X Receptor Results in Net Depletion of Cellular Cholesteryl Esters in Macrophages Exposed to Oxidized Lipoproteins Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 475 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mardones, A. Pilon, M. Bouly, D. Duran, T. Nishimoto, H. Arai, K. F. Kozarsky, M. Altayo, J. F. Miquel, G. Luc, et al. Fibrates Down-regulate Hepatic Scavenger Receptor Class B Type I Protein Expression in Mice J. Biol. Chem., February 28, 2003; 278(10): 7884 - 7890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Dello Russo, V. Gavrilyuk, G. Weinberg, A. Almeida, J. P. Bolanos, J. Palmer, D. Pelligrino, E. Galea, and D. L. Feinstein Peroxisome Proliferator-activated Receptor gamma Thiazolidinedione Agonists Increase Glucose Metabolism in Astrocytes J. Biol. Chem., February 14, 2003; 278(8): 5828 - 5836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Seda, L. Kazdova, D. Krenova, and V. Kren Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36-deficient BN.SHR4 congenic rat strain Physiol Genomics, January 15, 2003; 12(2): 73 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sasali and J. L. Leahy Is Metformin Cardioprotective? Diabetes Care, January 1, 2003; 26(1): 243 - 244. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||