(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
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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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 M. D. Ashen and R. S. Blumenthal Low HDL Cholesterol Levels N. Engl. J. Med., September 22, 2005; 353(12): 1252 - 1260. [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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 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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 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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L. Normen, J. Frohlich, J. Montaner, M. Harris, T. Elliott, and G. Bondy Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol Diabetes Care, September 1, 2004; 27(9): 2241 - 2242. [Full Text] [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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