(Circulation. 1998;98:2088-2093.)
© 1998 American Heart Association, Inc.
Cardiovascular Drugs |
Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism
From Unité 325 INSERM (B.S., J.D., J.A., K.S., J.-C.F.), Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France, and Center for Research, Prevention and Treatment of Atherosclerosis (E.L.), Division of Medicine, Hadassah University Hospital, 91120 Jerusalem, Israel.
Correspondence to Jean-Charles Fruchart, Département d'Athérosclérose et INSERM U325, Institut Pasteur de Lille, 1, rue du Prof. Calmette, 59019 Lille Cédex, France. E-mail Jean-Charles.Fruchart{at}pasteur-lille.fr
Abstract
Abstract—Treatment with
fibrates, a widely used class of lipid-modifying agents, results in a
substantial decrease in plasma triglycerides and is usually
associated with a moderate decrease in LDL cholesterol and
an increase in HDL cholesterol concentrations.
Recent investigations indicate that the effects of fibrates are
mediated, at least in part, through alterations in transcription of
genes encoding for proteins that control lipoprotein
metabolism. Fibrates activate specific
transcription factors belonging to the nuclear hormone receptor
superfamily, termed peroxisome proliferator-activated receptors
(PPARs). The PPAR-
form mediates fibrate action on HDL
cholesterol levels via transcriptional induction of
synthesis of the major HDL apolipoproteins, apoA-I and apoA-II.
Fibrates lower hepatic apoC-III production and increase
lipoprotein lipase—mediated lipolysis via PPAR. Fibrates stimulate
cellular fatty acid uptake, conversion to acyl-CoA derivatives, and
catabolism by the ß-oxidation pathways, which, combined with a
reduction in fatty acid and triglyceride synthesis, results
in a decrease in VLDL production. In summary, both enhanced
catabolism of triglyceride-rich particles and reduced
secretion of VLDL underlie the hypotriglyceridemic
effect of fibrates, whereas their effect on HDL metabolism
is associated with changes in HDL apolipoprotein expression.
Key Words: apolipoproteins • arteriosclerosis • fibrates • hypercholesterolemia • hyperlipoproteinemia • lipids • PPAR
A vast number of studies confirmed the intimate and
causative relationships between dyslipidemias and
coronary heart disease. Although
hypercholesterolemia is an important underlying
cause for coronary heart disease, other
dyslipidemias, such as hypoalphalipoproteinemia (low plasma
HDL) and hypertriglyceridemia, may be
causative in a substantial number of cases. Fibrates are useful for the
treatment of hypoalphalipoproteinemia with or without
hypertriglyceridemia.1 2
The recommendation for the use of fibrates in certain types of
dyslipidemia has gained additional support from a subgroup
analysis of the Helsinki Heart Study,3
which showed that the best preventive efficacy has been achieved in a
subset of 
10% of the study population who had a baseline LDL:HDL
cholesterol ratio of >5 and a triglyceride
level of 2.3 mmol/L.4 5 Results from
angiographic trials revealed that fibrates retard the progression of
coronary atherosclerosis and decrease the
number of coronary events.6 7
Pharmacological Action of Fibrates
Fibrates are generally effective in lowering elevated plasma triglycerides and cholesterol. The magnitude of lipid changes depends, however, on the patient's pretreatment lipoprotein status8 as well as the relative potency of the fibrate used.9 The most pronounced effects of fibrates are a decrease in plasma triglyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol (LDL-C) generally decrease in individuals with elevated baseline plasma concentrations, and HDL cholesterol (HDL-C) levels are usually increased when baseline plasma concentrations are low.8 However, paradoxical increases in LDL-C have been reported in some patients with dyslipidemia.10 Fibrate treatment results in a reduction of the LDL fraction of atherogenic small, dense particles with an equivalent increase in the intermediate subfraction.11 12 13 Within the triglyceride-rich apolipoprotein (apo) B-containing lipoproteins, fibrates efficiently reduce the apoC-III–containing particles,14 15 which are markers for increased risk for atherogenesis.16 The increased HDL concentrations after fibrates are generally reflected by increased plasma levels of apoA-I and apoA-II,14 15 a change that is associated with an increase in lipoprotein (Lp) A-I:A-II, and a decrease in LpA-I concentrations in patients treated with fenofibrate.14 15
Mechanisms of Action of Fibrates
Evidence from studies in rodents and in humans is available to
implicate 5 major mechanisms underlying the above-mentioned modulation
of lipoprotein phenotypes by fibrates:
1. Induction of lipoprotein lipolysis. Increased TRL lipolysis could be a reflection of changes in intrinsic lipoprotein lipase (LPL) activity17 or increased accessibility of TRLs for lipolysis by LPL owing to a reduction of TRL apoC-III content.18
2. Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production. In rodents, fibrates increase FA uptake and conversion to acyl-CoA by the liver owing to the induction of FA transporter protein (FATP)19 and acyl-CoA synthetase (ACS) activity.20 Induction of the ß-oxidation pathway with a concomitant decrease in FA synthesis by fibrates results in a lower availability of FAs for triglyceride synthesis, a process that is amplified by the inhibition of hormone-sensitive lipase in adipose tissue by fibrates.21
3. Increased removal of LDL particles. Fibrate treatment results in the formation of LDL with a higher affinity for the LDL receptor, which are thus catabolized more rapidly.11
4. Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL.22
5. Increase in HDL production and stimulation of reverse cholesterol transport. Fibrates increase the production of apoA-I and apoA-II in liver,23 24 which may contribute to the increase of plasma HDL concentrations and a more efficient reverse cholesterol transport.
Role of Transcription Factors in Mediating Fibrate Action
It has been known for several years that fibrates induce peroxisome proliferation in rodents.25 26 This process is linked to the induction of transcription of genes involved in peroxisomal ß-oxidation and is mediated by specific transcription factors, therefore termed peroxisome proliferator-activated receptors (PPARs).
The PPAR Family of Transcription Factors
PPARs are members of the superfamily of nuclear hormone receptors,
which are transcription factors transmitting signals that originate
from lipid-soluble factors (eg, hormones, vitamins, and FAs) to the
genome.25 26 Nuclear receptors recognize and bind
to DNA at specific sites, called response elements (REs), which consist
of derivatives of the AGGTCA sequence. During evolution, mutation,
duplication, and addition of flanking sequences have generated REs
distinctive for the various receptors. Once bound to its RE, the
receptor complex can activate or repress the expression of a
target gene.
PPARs heterodimerize with the retinoid X receptor (RXR) and bind to REs
arranged as direct repeats spaced by 1 nucleotide (DR1),
termed peroxisome proliferator response elements (PPREs)
(Figure
). To date, 3 different PPAR genes
(, 
[also termed ß, NUC I, or FAAR],
and 
) have been identified.25 PPARs display
distinct expression patterns, which suggests important functional
differences. PPAR- is predominantly expressed in tissues that
metabolize high amounts of FAs, such as liver, kidney, heart, and
muscle.27 The expression of PPAR- is high in
adipose tissue, where it triggers adipocyte differentiation and induces
the expression of genes critical for
adipogenesis.26
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FAs and derivatives, such as prostaglandin J2 for
PPAR-28 29 or
8(S)hydroxyeicosatetraenoic
acid,30 31
8(S)hydroxyeicosapentaenoic
acid,31 and leukotriene
B432 for PPAR-, have been implicated as
natural PPAR ligands. Fibrates are synthetic ligands for
PPAR-.30 31 32
In rodents, fibrates induce the expression of genes involved in
intracellular FA metabolism, such as peroxisomal and
mitochondrial ß-oxidation, 
-hydroxylation, and
ketogenesis.33 By contrast, very few data are
available on the regulation of their human counterparts, and it awaits
further study to determine whether fibrates and/or PPARs also regulate
the expression of any of these genes in humans. However, in contrast to
rodents, there is no evidence that fibrates would induce peroxisome
proliferation in humans and primates.34
The Role of PPARs in Mediating Fibrate Action on Lipoprotein
Metabolism in Humans
TRL Metabolism
The hypotriglyceridemic action of fibrates
involves combined effects on LPL17 and apoC-III
expression,34 resulting in increased lipolysis.
The induction of LPL expression occurs at the transcriptional level and
is mediated by PPAR. The latter binds to a PPRE that is present
both in the human and the mouse LPL gene
promoters.35
In contrast to LPL, transcription of the apoC-III gene is
inhibited by fibrates, resulting in decreased production of
apoC-III in the liver.34 The repression of
apoC-III gene expression by fibrates is mediated via
PPAR-.36 Consistent with the
repression of apoC-III expression, turnover studies in humans indicate
that fibrates reduce apoC-III synthesis,18
leading to enhanced LPL-mediated catabolism of VLDL particles.
Moreover, fibrates also decrease apoB and VLDL
production.37 As a consequence, a reduced
secretion of VLDL particles, together with the enhanced catabolism of
triglyceride-rich particles, most likely accounts for the
hypolipidemic effect of fibrates.
Animal studies suggest that fibrates also increase the hepatic uptake of free FAs (FFAs) by specific FATPs19 and generation of acyl-CoA esters by ACS.20 Owing to an increased ß-oxidation activity and a reduction in acetyl-CoA carboxylase and FA synthase activities,38 FFA metabolism is shifted from triglyceride synthesis to catabolism. Although fibrates do not induce peroxisomal ß-oxidation in humans, it is conceivable that they also affect FA uptake, conversion, and catabolism through the mitochondrial ß-oxidation pathway in humans.
HDL Metabolism
In humans, fibrates increase plasma levels of HDL and its major
constituents, apoA-I and apoA-II, to a variable
extent39 40 and stimulate apoA-I
production in human apoA-I transgenic mice and human
hepatocytes.24 In vitro studies have
demonstrated that the induction of human apoA-I gene expression after
fibrates may be mediated by the interaction of PPAR with a functional
PPRE, localized in the A site of the apoA-I
promoter.41 Human apoA-II plasma concentrations
increase after fibrate treatment.14 15 This is a
consequence of the induction of hepatic apoA-II synthesis by fibrates
and is mediated through PPAR/RXR heterodimers.23
Indications and Clinical Use of Fibrates in Specific Lipoprotein Disorders
Primary Hypertriglyceridemia
Fibrates are first-line drugs for the treatment of primary
hypertriglyceridemia. In these patients,
fibrates most noticeably decrease plasma TRLs42;
they also decrease, albeit to a lesser extent, total
cholesterol, whereas HDL-C levels
increase.42 The reduction in
cholesterol and triglycerides is mainly due to
a fall in VLDL, which is accompanied by changes in VLDL
composition.42 Fibrates predominantly reduce the
concentrations of large VLDL subfractions.43 44
In addition, fibrates attenuate the postprandial lipid response in
hypertriglyceridemic
subjects.44
LDL lipid composition is normalized in hypertriglyceridemic patients, who generally have low levels of LDL with an abnormal lipid composition.45 The cholesteryl ester content of LDL increases in all LDL subclasses, resulting in large, less-dense LDL particles.13 43 These changes lead to increased interactions of LDL particles with the LDL receptor, thereby improving LDL clearance.46
HDL-C levels, which are low in patients with hypertriglyceridemia, increase after treatment with fibrates.42 The lowering of the pool of TRLs on treatment with fibrates results in the reduction of net cholesteryl ester transfer from HDL to TRLs,22 which, in association with unchanged lecithin:cholesterol acyl transferase (LCAT) activity, will ultimately lead to an increase in cholesteryl ester and a decrease in triglyceride content of HDL. Improvement of LPL-mediated lipolysis of TRLs43 and increased apoA-I and apoA-II synthesis may also contribute to the rise in HDL levels on treatment with fibrates by promoting the formation of HDL precursors.
Type III Dysbetalipoproteinemia
Type III dysbetalipoproteinemia is a rare lipid disorder resulting
from homozygosity for the rare apoE2 isoform in predisposed subjects.
The characteristic disturbance of this metabolic
disorder is the accumulation of cholesterol-enriched VLDL,
which migrates in ß-position on agarose gel electrophoresis. Fibrates
have a spectacular lipid-lowering potential in patients with type III
dysbetalipoproteinemia.15 47 48 The levels of
circulating triglycerides and cholesterol are
greatly diminished. The reduction in cholesterol is
accounted for by the major reduction of VLDL cholesterol
(VLDL-C) and IDL cholesterol, the most atherogenic
lipoproteins in patients with type III dysbetalipoproteinemia.
Simultaneously, LDL-C and HDL-C, which are usually low,
increase significantly. As a consequence of the reduction in
ß-VLDL,15 regression of xanthoma and
improvement of manifestations of atherosclerosis are
observed 49
Combined Hyperlipidemia
Fibrates efficiently lower plasma cholesterol, VLDL-C,
and triglycerides and increase HDL-C in combined
hyperlipidemia.50 The reduction
in total cholesterol is accounted for by the fall in both
VLDL-C and LDL-C,51 whereas the reduction of
triglyceride levels is associated with normalization of the
typical atherogenic LDL subspecies profile in this lipid disorder.
Fibrate treatment reduces the levels of dense LDL and of
LDL-triglyceride content. Mean LDL peak particle size may
increase to normal or remain small,52 but the
mean LDL flotation rate augments because of an increase in buoyant LDL
concentration.52
Primary Hypercholesterolemia
Although fibrates are not considered to be first-line drugs in
primary
hypercholesterolemia,1 2
the new generation of fibrates efficiently reduce plasma
cholesterol and LDL-C and increase HDL-C concentrations
when used in monotherapy in patients with primary
hypercholesterolemia.51 53
However, it should be emphasized that the response of
hypercholesterolemic patients to fibrate treatment is
heterogenous, and nonresponse or even a paradoxical
increase in LDL has been observed.54 55 The
reduction in total cholesterol is accounted for by a fall
in both VLDL-C and LDL-C.53 Fibrates reduce the
dense LDL but not the light LDL fraction,56 57
which is less susceptible to oxidation.13 The
affinity of LDL for cellular receptors is not affected by treatment in
patients with primary
hypercholesterolemia.57
The increase in HDL-C is related to a lower cholesteryl ester transfer
protein activity, whereas LCAT activity is not
affected.57 In patients with primary
hypercholesterolemia, LPL activity also
increases on treatment with fibrates, resulting in a reduction of
postprandial lipemia.58
Non–Insulin-Dependent Diabetes Mellitus
In non–insulin-dependent diabetes mellitus (NIDDM) with
hyperlipemia, fibrates lower plasma cholesterol,
triglycerides, VLDL, and
IDL.54 59 60 61 The levels of apoC-III decrease,
resulting in improvement of TRL lipolysis and
clearance.59 62 The effect on LDL-C and apoB is
dependent on the concentration of plasma
TG.54 60 61 The mean LDL particle diameter
increases, whereas the concentration of dense LDL decreases in
proportion to the changes in
triglycerides.63 Fibrates increase
total HDL-C mainly owing to an elevation of the
HDL3 fraction.62 As in
patients with primary hyperlipemia, fibrates reduce postprandial
lipemia in patients with NIDDM.64
Tolerability and Safety
In general, fibrates are considered to be well tolerated, with an excellent safety profile. A low incidence of fibrate-associated toxicity has been reported in almost every organ system.65 In accordance with this notion, a summary of 10 years' experience with fenofibrate with an exposure of 6 million patient-years including 7145 patients involved in clinical trials revealed a low frequency of side effects.66
Members of the 2 most popular classes of lipid-lowering drugs, HMG CoA reductase inhibitors and fibrates, cause cancer in rodents.67 Although the mechanism may be related to peroxisome proliferation, a definite link has not yet been established. In humans, long-term administration of various fibrates does not cause peroxisome proliferation or any other morphological changes in the liver.68 69 Extrapolation of this evidence of carcinogenesis from rodents to humans is uncertain.
Clinically relevant interactions of fibrates with other antihyperlipidemic drugs include rhabdomyolysis (reported in combination with HMG CoA reductase inhibitors) and decreased bioavailability when combined with some bile acid sequestrants. Finally, potentiation of the anticoagulant effect of coumarin derivatives may cause bleeding.70
Future Perspectives
The better understanding of the basic mechanisms of action of
fibrates in both rodents and humans should now allow the development of
novel compounds on a more rational basis. Because the currently
available fibrates (Table) are
rather nonspecific activators of various PPARs, it is
expected that more potent and subtype-specific PPAR ligands and/or
activators might constitute a novel class of
"superfibrates." These compounds might enhance specificity, reduce
side effects, and widen the clinical indications of this class of
lipid-lowering drugs. Ongoing large clinical studies should confirm
their effectiveness in reducing coronary events and demonstrate
a possible benefit on coronary and total mortality.
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Acknowledgments
Dr Schoonjans was supported by fellowships from ARC and IFN; Drs Auwerx and Staels are members of the CNRS. This work was supported by INSERM U325, Institut Pasteur De Lille, Région Nord, Pas-de-Calais.
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 L. Tenkanen, M. Manttari, P. T. Kovanen, H. Virkkunen, and V. Manninen Gemfibrozil in the Treatment of Dyslipidemia: An 18-Year Mortality Follow-up of the Helsinki Heart Study. Arch Intern Med, April 10, 2006; 166(7): 743 - 748. [Abstract] [Full Text] [PDF]
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S. Bilz, V. Samuel, K. Morino, D. Savage, C. S. Choi, and G. I. Shulman Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E716 - E722. [Abstract] [Full Text] [PDF]
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R. Paumelle, C. Blanquart, O. Briand, O. Barbier, C. Duhem, G. Woerly, F. Percevault, J.-C. Fruchart, D. Dombrowicz, C. Glineur, et al. Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator-Activated Receptor-{alpha} via Inhibition of the Protein Kinase C Signaling Pathway Circ. Res., February 17, 2006; 98(3): 361 - 369. [Abstract] [Full Text] [PDF]
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 R. Di Paola, E. Mazzon, D. Maiere, D. Zito, D. Britti, M. De Majo, T. Genovese, and S. Cuzzocrea Rosiglitazone Reduces the Evolution of Experimental Periodontitis in the Rat Journal of Dental Research, February 1, 2006; 85(2): 156 - 161. [Abstract] [Full Text] [PDF]
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C.-H. Lee and J. Plutzky Liver X Receptor Activation and High-Density Lipoprotein Biology: A Reversal of Fortune? Circulation, January 3, 2006; 113(1): 5 - 8. [Full Text] [PDF]
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Evolving treatment paradigms for vascular risk reduction in type 2 diabetes: Report of an international symposium held in Barcelona, Spain, January 27-29, 2006 The British Journal of Diabetes & Vascular Disease, January 1, 2006; 6(1_suppl): S1 - S12. [PDF]
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F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]
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G. Chinetti-Gbaguidi, E. Rigamonti, L. Helin, A. L. Mutka, M. Lepore, J. C. Fruchart, V. Clavey, E. Ikonen, S. Lestavel, and B. Staels Peroxisome proliferator-activated receptor {alpha} controls cellular cholesterol trafficking in macrophages J. Lipid Res., December 1, 2005; 46(12): 2717 - 2725. [Abstract] [Full Text] [PDF]
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T. C. Martinsen, I. Bakke, D. Chen, A. K. Sandvik, K. Zahlsen, T. Aamo, and H. L. Waldum Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-{alpha} Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G1052 - G1060. [Abstract] [Full Text] [PDF]
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I. L. Ruel, B. Lamarche, J.-F. Mauger, K. O. Badellino, J. S. Cohn, M. Marcil, and P. Couture Effect of Fenofibrate on Plasma Lipoprotein Composition and Kinetics in Patients With Complete Hepatic Lipase Deficiency Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2600 - 2607. [Abstract] [Full Text] [PDF]
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B. Fletcher, K. Berra, P. Ades, L. T. Braun, L. E. Burke, J. L. Durstine, J. M. Fair, G. F. Fletcher, D. Goff, L. L. Hayman, et al. Managing Abnormal Blood Lipids: A Collaborative Approach Circulation, November 15, 2005; 112(20): 3184 - 3209. [Abstract] [Full Text] [PDF]
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N. F. Cariello, E. H. Romach, H. M. Colton, H. Ni, L. Yoon, J. G. Falls, W. Casey, D. Creech, S. P. Anderson, G. R. Benavides, et al. Gene Expression Profiling of the PPAR-alpha Agonist Ciprofibrate in the Cynomolgus Monkey Liver Toxicol. Sci., November 1, 2005; 88(1): 250 - 264. [Abstract] [Full Text] [PDF]
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T. Claudel, B. Staels, and F. Kuipers The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2020 - 2030. [Abstract] [Full Text] [PDF]
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C. Kjorholt, M. C. Akerfeldt, T. J. Biden, and D. R. Laybutt Chronic Hyperglycemia, Independent of Plasma Lipid Levels, Is Sufficient for the Loss of {beta}-Cell Differentiation and Secretory Function in the db/db Mouse Model of Diabetes Diabetes, September 1, 2005; 54(9): 2755 - 2763. [Abstract] [Full Text] [PDF]
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P.J. Barter Antiatherogenic Properties of Fibrates Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1095 - 1096. [Full Text] [PDF]
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R. Arakawa, N. Tamehiro, T. Nishimaki-Mogami, K. Ueda, and S. Yokoyama Fenofibric Acid, an Active Form of Fenofibrate, Increases Apolipoprotein A-I-Mediated High-Density Lipoprotein Biogenesis by Enhancing Transcription of ATP-Binding Cassette Transporter A1 Gene in a Liver X Receptor-Dependent Manner Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1193 - 1197. [Abstract] [Full Text] [PDF]
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 G D Kolovou, K K Anagnostopoulou, and D V Cokkinos Pathophysiology of dyslipidaemia in the metabolic syndrome Postgrad. Med. J., June 1, 2005; 81(956): 358 - 366. [Abstract] [Full Text] [PDF]
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 J. A. Wagner, P. J. Larson, S. Weiss, J. L. Miller, T. W. Doebber, M. S. Wu, D. E. Moller, and K. M. Gottesdiener Individual and Combined Effects of Peroxisome Proliferator-Activated Receptor and {gamma} Agonists, Fenofibrate and Rosiglitazone, on Biomarkers of Lipid and Glucose Metabolism in Healthy Nondiabetic Volunteers J. Clin. Pharmacol., May 1, 2005; 45(5): 504 - 513. [Abstract] [Full Text] [PDF]
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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]
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 A.-M. Paradis, B. Fontaine-Bisson, Y. Bosse, J. Robitaille, S. Lemieux, H. Jacques, B. Lamarche, A. Tchernof, P. Couture, and M.-C. Vohl The peroxisome proliferator-activated receptor {alpha} Leu162Val polymorphism influences the metabolic response to a dietary intervention altering fatty acid proportions in healthy men Am. J. Clinical Nutrition, February 1, 2005; 81(2): 523 - 530. [Abstract] [Full Text] [PDF]
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V. Sheena, R. Hertz, J. Nousbeck, I. Berman, J. Magenheim, and J. Bar-Tana Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4{alpha} J. Lipid Res., February 1, 2005; 46(2): 328 - 341. [Abstract] [Full Text] [PDF]
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D. V. Erbe, S. Wang, Y.-L. Zhang, K. Harding, L. Kung, M. Tam, L. Stolz, Y. Xing, S. Furey, A. Qadri, et al. Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms Mol. Pharmacol., January 1, 2005; 67(1): 69 - 77. [Abstract] [Full Text] [PDF]
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 T. C. McCarthy, P. T. Pollak, E. A. Hanniman, and C. J. Sinal Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-{alpha}Target Gene Activation J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 864 - 873. [Abstract] [Full Text] [PDF]
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 J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]
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Y. Guan Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2801 - 2815. [Abstract] [Full Text] [PDF]
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D. Walcher and N. Marx Insulin resistance and cardiovascular disease: the role of PPAR{gamma} activators beyond their anti-diabetic action Diabetes and Vascular Disease Research, October 1, 2004; 1(2): 76 - 81. [Abstract] [PDF]
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G. Boden and M. Laakso Lipids and Glucose in Type 2 Diabetes: What is the cause and effect? Diabetes Care, September 1, 2004; 27(9): 2253 - 2259. [Full Text] [PDF]
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T. P. Beyer, R. J. Schmidt, P. Foxworthy, Y. Zhang, J. Dai, W. R. Bensch, R. F. Kauffman, H. Gao, T. P. Ryan, X.-C. Jiang, et al. Coadministration of a Liver X Receptor Agonist and a Peroxisome Proliferator Activator Receptor-{alpha} Agonist in Mice: Effects of Nuclear Receptor Interplay on High-Density Lipoprotein and Triglyceride Metabolism in Vivo J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 861 - 868. [Abstract] [Full Text] [PDF]
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N. Marx, H. Duez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circ. Res., May 14, 2004; 94(9): 1168 - 1178. [Abstract] [Full Text] [PDF]
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T.B. Twickler, G.M. Dallinga-Thie, J.S. Cohn, and M.J. Chapman Elevated Remnant-Like Particle Cholesterol Concentration: A Characteristic Feature of the Atherogenic Lipoprotein Phenotype Circulation, April 27, 2004; 109(16): 1918 - 1925. [Full Text] [PDF]
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K. Goya, S. Sumitani, X. Xu, T. Kitamura, H. Yamamoto, S. Kurebayashi, H. Saito, H. Kouhara, S. Kasayama, and I. Kawase Peroxisome Proliferator-Activated Receptor {alpha} Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 658 - 663. [Abstract] [Full Text] [PDF]
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S. M. Post, M. Groenendijk, K. Solaas, P. C. N. Rensen, and H. M. G. Princen Cholesterol 7{alpha}-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 768 - 774. [Abstract] [Full Text] [PDF]
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M. Ricote, A. F. Valledor, and C. K. Glass Decoding Transcriptional Programs Regulated by PPARs and LXRs in the Macrophage: Effects on Lipid Homeostasis, Inflammation, and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 230 - 239. [Abstract] [Full Text]
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M. C. Sugden and M. J. Holness Potential Role of Peroxisome Proliferator-Activated Receptor-{alpha} in the Modulation of Glucose-Stimulated Insulin Secretion Diabetes, February 1, 2004; 53(90001): S71 - 81. [Abstract] [Full Text]
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S. Bilz, S. Wagner, M. Schmitz, A. Bedynek, U. Keller, and T. Demant Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia J. Lipid Res., January 1, 2004; 45(1): 174 - 185. [Abstract] [Full Text] [PDF]
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I. J. A. M. Jonkers, A. H. M. Smelt, H. Hattori, L. M. Scheek, T. van Gent, F. H. A. F. de Man, A. van der Laarse, and A. van Tol Decreased PLTP mass but elevated PLTP activity linked to insulin resistance in HTG: effects of bezafibrate therapy J. Lipid Res., August 1, 2003; 44(8): 1462 - 1469. [Abstract] [Full Text] [PDF]
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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]
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G. A. Francis, J.-S. Annicotte, and J. Auwerx PPAR-{alpha} effects on the heart and other vascular tissues Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H1 - H9. [Abstract] [Full Text] [PDF]
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J.-P. Despres, I. Lemieux, A. Pascot, N. Almeras, M. Dumont, A. Nadeau, J. Bergeron, and D. Prud'homme Gemfibrozil Reduces Plasma C-Reactive Protein Levels in Abdominally Obese Men With the Atherogenic Dyslipidemia of the Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 702 - 703. [Full Text] [PDF]
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C. Gouedard, N. Koum-Besson, R. Barouki, and Y. Morel Opposite Regulation of the Human Paraoxonase-1 Gene PON-1 by Fenofibrate and Statins Mol. Pharmacol., April 1, 2003; 63(4): 945 - 956. [Abstract] [Full Text] [PDF]
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C. L. Brand, J. Sturis, C. F. Gotfredsen, J. Fleckner, C. Fledelius, B. F. Hansen, B. Andersen, J.-M. Ye, P. Sauerberg, and K. Wassermann Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E841 - E854. [Abstract] [Full Text] [PDF]
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G. F. Watts, P. H. R. Barrett, J. Ji, A. P. Serone, D. C. Chan, K. D. Croft, F. Loehrer, and A. G. Johnson Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome Diabetes, March 1, 2003; 52(3): 803 - 811. [Abstract] [Full Text] [PDF]
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