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Titolo:
Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha
Autore:
Kockx, M; Gervois, PP; Poulain, P; Derudas, B; Peters, JM; Gonzalez, FJ; Princen, HMG; Kooistra, T; Staels, B;
Indirizzi:
TNO Prevent & Hlth, Gaubius Lab, NL-2301 CE Leiden, Netherlands TNO Prevent & Hlth Leiden Netherlands NL-2301 CE CE Leiden, Netherlands Inst Pasteur, INSERM, U325, Dept Atherosclerose, F-59019 Lille, France Inst Pasteur Lille France F-59019 Atherosclerose, F-59019 Lille, France Univ Lille 2, Fac Pharm, Lille, France Univ Lille 2 Lille FranceUniv Lille 2, Fac Pharm, Lille, France NCI, Lab Metab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Lab Metab, NIH, Bethesda, MD 20892 USA
Titolo Testata:
BLOOD
fascicolo: 9, volume: 93, anno: 1999,
pagine: 2991 - 2998
SICI:
0006-4971(19990501)93:9<2991:FSFGEI>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
CORONARY HEART-DISEASE; PPAR-GAMMA ACTIVATORS; LIPOPROTEIN METABOLISM; RESPONSE ELEMENT; FATTY-ACIDS; PROMOTER; MICE; RAT; HYPERCHOLESTEROLEMIA; HEPATOCYTES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Kooistra, T TNO Prevent & Hlth, Gaubius Lab, POB 2215, NL-2301 CE Leiden, Netherlands TNO Prevent & Hlth POB 2215 Leiden Netherlands NL-2301 CE nds
Citazione:
M. Kockx et al., "Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha", BLOOD, 93(9), 1999, pp. 2991-2998

Abstract

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 alpha-, B beta-, and gamma-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 alpha-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-alpha (PPAR alpha) because a high-affinity ligand for PPAR gamma, the thiazolidinedioneBRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPAR alpha in the suppression of fibrinogen by fibrates was obtained using PPAR alpha-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 alpha-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 alpha-chain mRNA levels to 65% +/- 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPAR alpha regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPAR alpha. (C) 1999 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 17:43:12