|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2991-2998
Fibrates Suppress Fibrinogen Gene Expression in Rodents Via
Activation of the Peroxisome Proliferator-Activated Receptor-
Maaike Kockx,
Philippe P. Gervois,
Philippe Poulain,
Bruno Derudas,
Jeffrey M. Peters,
Frank J. Gonzalez,
Hans M.G. Princen,
Teake Kooistra, and
Bart Staels
From Gaubius Laboratory, TNO-Prevention and Health, Leiden, The
Netherlands; U.325 INSERM, Département d'Athérosclerose,
Institut Pasteur, Lille; Faculté de Pharmacie, Université
de Lille II, Lille, France; and the Laboratory of Metabolism, National
Cancer Institute, National Institutes of Health, Bethesda,
MD.
Plasma fibrinogen levels have been identified as an important risk
factor for cardiovascular diseases. Among the few compounds known to
lower circulating fibrinogen levels in humans are certain fibrates. We
have studied the regulation of fibrinogen gene expression by fibrates
in rodents. Treatment of adult male rats with fenofibrate (0.5%
[wt/wt] in the diet) for 7 days decreased hepatic A -, B -, and
 -chain mRNA levels to 52% ± 7%, 46% ± 8%, and 81% ± 19%
of control values, respectively. In parallel, plasma fibrinogen
concentrations were decreased to 63% ± 7% of controls. The
suppression of fibrinogen expression was dose-dependent and was already
evident after 1 day at the highest dose of fenofibrate tested (0.5%
[wt/wt]). Nuclear run-on experiments showed that the decrease in
fibrinogen expression after fenofibrate occurred at the transcriptional
level, as exemplified for the gene for the A-chain. Other fibrates
tested showed similar effects on fibrinogen expression and
transcription. The effect of fibrates is specific for peroxisome
proliferator-activated receptor- (PPAR) because a high-affinity
ligand for PPAR, the thiazolidinedione BRL 49653, lowered
triglyceride levels, but was unable to suppress fibrinogen expression.
Direct evidence for the involvement of PPAR in the suppression of
fibrinogen by fibrates was obtained using PPAR-null ( /) mice.
Compared with (+/+) mice, plasma fibrinogen levels in (/)
mice were significantly higher (3.20 ± 0.48 v 2.67 ± 0.42 g/L). Also, hepatic fibrinogen A-chain mRNA levels were 25% ± 11% higher in the (/) mice. On treatment with 0.2% (wt/wt)
fenofibrate, a significant decrease in plasma fibrinogen to 77% ± 10% of control levels and in hepatic fibrinogen A-chain mRNA levels
to 65% ± 12% of control levels was seen in (+/+) mice, but not
in (/) mice. These studies show that PPAR regulates basal
levels of plasma fibrinogen and establish that fibrate-suppressed
expression of fibrinogen in rodents is mediated through PPAR.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
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]
|
|
|
|
|
|
|
M. Westerterp, J. F.P. Berbee, N. M.M. Pires, G. J.D. van Mierlo, R. Kleemann, J. A. Romijn, L. M. Havekes, and P. C.N. Rensen
Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E Knockout Mice
Circulation,
November 6, 2007;
116(19):
2173 - 2181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Michalik, J. Auwerx, J. P. Berger, V. K. Chatterjee, C. K. Glass, F. J. Gonzalez, P. A. Grimaldi, T. Kadowaki, M. A. Lazar, S. O'Rahilly, et al.
International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors
Pharmacol. Rev.,
December 1, 2006;
58(4):
726 - 741.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. M. Zadelaar, L. S.M. Boesten, J. W. Jukema, B. J.M. van Vlijmen, T. Kooistra, J. J. Emeis, E. Lundholm, G. Camejo, and L. M. Havekes
Dual PPAR{alpha}/{gamma} Agonist Tesaglitazar Reduces Atherosclerosis in Insulin-Resistant and Hypercholesterolemic ApoE*3Leiden Mice
Arterioscler Thromb Vasc Biol,
November 1, 2006;
26(11):
2560 - 2566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S. M. Boesten, A. S. M. Zadelaar, A. van Nieuwkoop, L. Hu, J. Jonkers, B. van de Water, M. J. J. Gijbels, I. van der Made, M. P. J. de Winther, L. M. Havekes, et al.
Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice
FASEB J,
May 1, 2006;
20(7):
953 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Dorr, D. M. Robinson, H. Wallaschofski, C. Schwahn, U. John, S. B. Felix, and H. Volzke
Low Serum Thyrotropin Is Associated with High Plasma Fibrinogen
J. Clin. Endocrinol. Metab.,
February 1, 2006;
91(2):
530 - 534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Chauvet, B. Bois-Joyeux, C. Fontaine, P. Gervois, M.-A. Bernard, B. Staels, and J.-L. Danan
The Gene Encoding Fibrinogen-{beta} Is a Target for Retinoic Acid Receptor-Related Orphan Receptor {alpha}
Mol. Endocrinol.,
October 1, 2005;
19(10):
2517 - 2526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Hennuyer, A. Tailleux, G. Torpier, H. Mezdour, J.-C. Fruchart, B. Staels, and C. Fievet
PPAR{alpha}, but not PPAR{gamma}, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia
Arterioscler Thromb Vasc Biol,
September 1, 2005;
25(9):
1897 - 1902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Currie, V. Bombail, J. D. Oliver, D. J. Moore, F. L. Lim, V. Gwilliam, I. Kimber, K. Chipman, J. G. Moggs, and G. Orphanides
Gene Ontology Mapping as an Unbiased Method for Identifying Molecular Pathways and Processes Affected by Toxicant Exposure: Application to Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate
Toxicol. Sci.,
August 1, 2005;
86(2):
453 - 469.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-h. Shih, S.-L. Chen, C.-C. Yen, Y.-H. Huang, C.-d. Chen, Y.-S. Lee, and K.-h. Lin
Thyroid Hormone Receptor-Dependent Transcriptional Regulation of Fibrinogen and Coagulation Proteins
Endocrinology,
June 1, 2004;
145(6):
2804 - 2814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gervois, R. Kleemann, A. Pilon, F. Percevault, W. Koenig, B. Staels, and T. Kooistra
Global Suppression of IL-6-induced Acute Phase Response Gene Expression after Chronic in Vivo Treatment with the Peroxisome Proliferator-activated Receptor-{alpha} Activator Fenofibrate
J. Biol. Chem.,
April 16, 2004;
279(16):
16154 - 16160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kleemann, H. M.G. Princen, J. J. Emeis, J. W. Jukema, R. D. Fontijn, A. J.G. Horrevoets, T. Kooistra, and L. M. Havekes
Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol-Lowering Effect in APOE*3-Leiden Transgenic Mice: Evidence for Antiinflammatory Effects of Rosuvastatin
Circulation,
September 16, 2003;
108(11):
1368 - 1374.
[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]
|
|
|
|
|
|
|
W. H Reinhart
Fibrinogen - marker or mediator of vascular disease?
Vascular Medicine,
August 1, 2003;
8(3):
211 - 216.
[Abstract]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
H. S. Sood, M. J. Hunt, and S. C. Tyagi
Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia
Am J Physiol Lung Cell Mol Physiol,
February 1, 2003;
284(2):
L333 - L341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kleemann, P. P. Gervois, L. Verschuren, B. Staels, H. M. G. Princen, and T. Kooistra
Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation
Blood,
January 15, 2003;
101(2):
545 - 551.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Kluft, R. Kleemann, and M.P.M. de Maat
How best to counteract the enemies? By controlling inflammation in the coronary circulation
Eur. Heart J. Suppl.,
November 1, 2002;
4(suppl_G):
G53 - G65.
[Abstract]
[PDF]
|
|
|
|
|
|
|
I. J. Waterman and V. A. Zammit
Differential Effects of Fenofibrate or Simvastatin Treatment of Rats on Hepatic Microsomal Overt and Latent Diacylglycerol Acyltransferase Activities
Diabetes,
June 1, 2002;
51(6):
1708 - 1713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Post, H. Duez, P. P. Gervois, B. Staels, F. Kuipers, and H. M.G. Princen
Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator-Activated Receptor-{alpha}-Mediated Downregulation of Cholesterol 7{alpha}-Hydroxylase and Sterol 27-Hydroxylase Expression
Arterioscler Thromb Vasc Biol,
November 1, 2001;
21(11):
1840 - 1845.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. Akiyama, C. J. Nicol, C. Fievet, B. Staels, J. M. Ward, J. Auwerx, S. S. T. Lee, F. J. Gonzalez, and J. M. Peters
Peroxisome Proliferator-activated Receptor-alpha Regulates Lipid Homeostasis, but Is Not Associated with Obesity. STUDIES WITH CONGENIC MOUSE LINES
J. Biol. Chem.,
October 12, 2001;
276(42):
39088 - 39093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. KERSTEN, S. MANDARD, P. ESCHER, F. J. GONZALEZ, S. TAFURI, B. DESVERGNE, and W. WAHLI
The peroxisome proliferator-activated receptor {alpha} regulates amino acid metabolism
FASEB J,
September 1, 2001;
15(11):
1971 - 1978.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. De Sutter, R. Tavernier, M. De Buyzere, L. Jordaens, and G. De Backer
Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients
J. Am. Coll. Cardiol.,
September 1, 2000;
36(3):
766 - 772.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gervois, N. Vu-Dac, R. Kleemann, M. Kockx, G. Dubois, B. Laine, V. Kosykh, J.-C. Fruchart, T. Kooistra, and B. Staels
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.,
August 31, 2001;
276(36):
33471 - 33477.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl
Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice
J. Biol. Chem.,
October 26, 2001;
276(44):
41293 - 41300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
