This Article Full Text Full Text (PDF) All Versions of this Article: 26/5/977    most recent 01.ATV.0000204327.96431.9av1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zambon, A. Articles by Staels, B. Search for Related Content PubMed PubMed Citation Articles by Zambon, A. Articles by Staels, B.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:977.)
© 2006 American Heart Association, Inc.

Brief Reviews

Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR– Activators

Clinical and Experimental Evidence

Alberto Zambon; Philippe Gervois; Paolo Pauletto; Jean-Charles Fruchart; Bart Staels

From Institut Pasteur de Lille (P.G., J.-C.F., B.S.), Département d’Athérosclerose, Lille, France; Inserm (P.G., J.-C.F., B.S.), U.545, Lille, France; Université de Lille 2 (P.G., J.-C.F., B.S.), Lille, France; Department of Medical and Surgical Sciences (A.Z., P.P.), Clinica Medica 1, University of Padua, Padua, Italy.

Correspondence to Phillipe Gervois, Université de Lille 2, Pasteur Institute, 1 rue du Prof Calmette, Lille, 59019 France. E-mail philippe.gervois{at}univ-lille2.fr

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)- and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)- is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR- is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR- agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR- agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR- activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR- agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor- and interleukin-6. Peroxisome proliferator-activated receptor (PPAR-)- is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR- is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR- agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21^st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Key Words: atherosclerosis • C-reactive protein • fibrates • inflammation • peroxisome proliferator-activated receptors

This article has been cited by other articles:

				A. Amoruso, C. Bardelli, L. G. Fresu, A. Palma, M. Vidali, V. Ferrero, F. Ribichini, C. Vassanelli, and S. Brunelleschi Enhanced Peroxisome Proliferator-Activated Receptor-{gamma} Expression in Monocyte/Macrophages from Coronary Artery Disease Patients and Possible Gender Differences J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 531 - 538. [Abstract] [Full Text] [PDF]

				M. J. Chapman, W. Le Goff, M. Guerin, and A. Kontush Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors Eur. Heart J., October 12, 2009; (2009) ehp399v1. [Abstract] [Full Text] [PDF]

				L. Makowski, R. C. Noland, T. R. Koves, W. Xing, O. R. Ilkayeva, M. J. Muehlbauer, R. D. Stevens, and D. M. Muoio Metabolic profiling of PPAR{alpha}-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation FASEB J, February 1, 2009; 23(2): 586 - 604. [Abstract] [Full Text] [PDF]

				C. D. Kane, K. A. Stevens, J. E. Fischer, M. Haghpassand, L. J. Royer, C. Aldinger, K. T. Landschulz, P. Zagouras, S. W. Bagley, W. Hada, et al. Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor {alpha} Agonists with Robust Hypolipidemic Activity in Vivo Mol. Pharmacol., February 1, 2009; 75(2): 296 - 306. [Abstract] [Full Text] [PDF]

				N. Stefan, K. Kantartzis, and H.-U. Haring Causes and Metabolic Consequences of Fatty Liver Endocr. Rev., December 1, 2008; 29(7): 939 - 960. [Abstract] [Full Text] [PDF]

				R. M. Mansouri, E. Bauge, B. Staels, and P. Gervois Systemic and Distal Repercussions of Liver-Specific Peroxisome Proliferator-Activated Receptor-{alpha} Control of the Acute-Phase Response Endocrinology, June 1, 2008; 149(6): 3215 - 3223. [Abstract] [Full Text] [PDF]

				P. Dandona Effects of Antidiabetic and Antihyperlipidemic Agents on C-Reactive Protein Mayo Clin. Proc., March 1, 2008; 83(3): 333 - 342. [Abstract] [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]

				L. Baud and E. Letavernier PPAR{alpha} Contributes to Tubular Protection J. Am. Soc. Nephrol., December 1, 2007; 18(12): 3017 - 3018. [Full Text] [PDF]

				A. Yessoufou, A. Hichami, P. Besnard, K. Moutairou, and N. A. Khan Peroxisome Proliferator-Activated Receptor {alpha} Deficiency Increases the Risk of Maternal Abortion and Neonatal Mortality in Murine Pregnancy with or without Diabetes Mellitus: Modulation of T Cell Differentiation Endocrinology, September 1, 2006; 147(9): 4410 - 4418. [Abstract] [Full Text] [PDF]