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Amirhossein Sahebkar - One of the best experts on this subject based on the ideXlab platform.
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effect of Fibrates on glycemic parameters a systematic review and meta analysis of randomized placebo controlled trials
Pharmacological Research, 2017Co-Authors: Luis E Simentalmendia, Mario Simentalmendia, Adriana Sanchezgarcia, Maciej Banach, Stephen L Atkin, Antonio M Gotto, Amirhossein SahebkarAbstract:Aims The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of Fibrates on glycemic parameters. Materials and methods Only randomized placebo-controlled trials investigating the impact of fibrate treatment on glucose homeostasis markers were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 11, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. Results This meta-analysis of data from 22 randomized placebo-controlled clinical trials involving a total of 11,402 subjects showed that fibrate therapy significantly decreased fasting plasma glucose (WMD: -0.28 mmol/L, 95% CI: -0.42, -0.14, p Conclusion This meta-analysis has shown that fibrate treatment significantly decreases fasting plasma glucose, insulin levels, and HOMA-IR indicating additional clinical therapeutic benefits.
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fibrate therapy and flow mediated dilation a systematic review and meta analysis of randomized placebo controlled trials
Pharmacological Research, 2016Co-Authors: Amirhossein Sahebkar, Renato Giua, Claudio Pedone, Kausik K Ray, Antonio J Vallejovaz, Luisa CostanzoAbstract:Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of Fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of Fibrates on endothelial function as estimated by FMD. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p 8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p<0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with Fibrates. The results of this meta-analysis suggest that Fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course.
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plasma uric acid concentrations are reduced by fenofibrate a systematic review and meta analysis of randomized placebo controlled trials
Pharmacological Research, 2015Co-Authors: Giuseppe Derosa, Amirhossein Sahebkar, Pamela MaffioliAbstract:Abstract Background Hyperuricaemia increases the risk of gout, but it is also a risk factor for cardiovascular diseases. Purpose To conduct a systematic review and meta-analysis of relevant randomized clinical trials to ascertain the effect size of Fibrates in modulating plasma uric acid concentrations. Data sources Medline ( http://www.ncbi.nlm.nih.gov/pubmed ), SCOPUS, Web of Science and Google Scholar databases were searched. Study selection Studies were included if they met the following inclusion criteria: (i) being a randomized placebo-controlled trial with either parallel or cross-over design, (ii) investigating the impact of fibrate therapy on plasma uric acid concentrations, (iii) presentation of sufficient information on uric acid values at baseline and at the end of follow-up in each group or providing the net change values. Data extraction The following data were extracted: (1) first author’s name; (2) year of publication; (3) study location; (4) study design; (5) number of participants in the fibrate and placebo groups; (6) type and dose of fibrate; (7) duration of treatment; (8) age, gender and body mass index (BMI) of study participants; (9) baseline levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, high-sensitivity C-reactive protein (hs-CRP) and glucose; (10) systolic and diastolic blood pressure; and (11) data regarding baseline and follow-up uric acid. Data synthesis There was a significant reduction in plasma uric acid concentrations following fenofibrate therapy. Limitations Few eligible studies, and most had small population sizes. Conclusions Fenofibrate, but not bezafibrate is effective in reducing serum acid uric levels.
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impact of fibrate therapy on plasma plasminogen activator inhibitor 1 a systematic review and meta analysis of randomized controlled trials
Atherosclerosis, 2015Co-Authors: Amirhossein Sahebkar, Luis E Simentalmendia, Gerald F Watts, Jonathan GolledgeAbstract:Abstract Objective The aim of this systematic review was to perform a meta-analysis of randomized controlled trials (RCTs) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 (PAI-1). Methods Scopus and MEDLINE databases were searched (up to October 15, 2014) to identify RCTs investigating whether Fibrates lower plasma PAI-1 concentration or activity. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed to assess the impact of potential moderators on the estimated effect sizes. Results A total of 14 RCTs examining the effects of gemfibrozil (6 trials), bezafibrate (4 trials), and fenofibrate (5 trials) were included. Meta-analysis suggested that fibrate therapy did not significantly reduce plasma PAI-1 concentration (weighed mean difference [WMD]: −11.39 ng/mL, 95% CI: −26.64, 3.85, p = 0.143) or activity (WMD: 2.02 U/mL, 95% CI: −0.87, 4.90, p = 0.170). These results remained unchanged after subgroup analysis according to duration of treatment ( Conclusion This meta-analysis of RCTs suggested that fibrate therapy does not reduce plasma concentration or activity of PAI-I. The putative benefits of fibrate therapy in patients with cardiovascular disease appear to be exerted via mechanisms independent of effects on PAI-1.
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circulating levels of proprotein convertase subtilisin kexin type 9 are elevated by fibrate therapy a systematic review and meta analysis of clinical trials
Cardiology in Review, 2014Co-Authors: Amirhossein SahebkarAbstract:Proprotein convertase subtilisin kexin type 9 (PCSK9) affects lipid metabolism through modulation of low-density lipoprotein (LDL) receptor degradation. Circulating PCSK9 status is an important determinant of LDL-cholesterol levels and is thus implicated in atherogenesis. The present study aimed to resolve inconsistencies in clinical findings on the impact of fibrate therapy on circulating PCSK9 concentrations using a meta-analysis of all published studies. A comprehensive literature search in Medline and Scopus was carried out to identify clinical reports on the impact of treatment with Fibrates on circulating concentrations of PCSK9. A meta-analysis of eligible studies was performed using a random-effects model. A weighed mean difference (WMD) with 95% confidence interval (CI) was used to assess the magnitude of Fibrates' effect on PCSK9 concentrations. Six studies comprising 218 subjects fulfilled the eligibility criteria and were included for systematic review and quantitative data synthesis. A meta-analysis indicated a significant elevation of circulating PCSK9 concentrations following fibrate therapy (WMD: +60.37; 95% CI: 11.04-109.71; P = 0.02). The PCSK9-elevating effect of Fibrates remained significant after comparison with a control group receiving either placebo or a statin (WMD: +23.97; 95% CI: 5.68-42.26; P = 0.01). Meta-regression analysis indicated that the effect size of Fibrates in modulating circulating PCSK9 levels is not dependent on the duration of treatment (point estimate for slope = 0.59, SE = 4.56; 95% CI = -8.34 to 9.53; z = 0.130, P = 0.897). Fibrate therapy is associated with a significant increase in circulating PCSK9 concentrations. Such a PCSK9 elevation may partly explain the modest efficacy of Fibrates on LDL-C.
Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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Fibrates suppress bile acid synthesis via peroxisome proliferator activated receptor α mediated downregulation of cholesterol 7α hydroxylase and sterol 27 hydroxylase expression
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: S M Post, Bart Staels, Helene Duez, Philippe Gervois, Folkert Kuipers, Hans M.g. PrincenAbstract:Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of Fibrates on bile acid synthesis. Ciprofibrate and the PPARalpha agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7alpha-hydroxylase enzyme activity and mRNA. The functional involvement of PPARalpha in the suppression of both enzymes was proven with the use of PPARalpha-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARalpha-null mice. A decreased bile acid production by PPARalpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
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induction of iκbα expression as a mechanism contributing to the anti inflammatory activities of peroxisome proliferator activated receptor α activators
Journal of Biological Chemistry, 2000Co-Authors: Philippe Delerive, Philippe Gervois, Jean-charles Fruchart, Bart StaelsAbstract:Abstract Chronic inflammation is a hallmark of degenerative diseases such as atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily, which are expressed in the cells of the atherosclerosic lesion. PPARα ligands have been reported to exert anti-inflammatory activities in different cell types by antagonizing the transcriptional activity of NF-κB. In the present study, the influence of PPARα activators on the NF-κB signaling pathway was investigated. Our results show that Fibrates, synthetic PPARα activators, induced the expression of the inhibitory protein IκBα in human aortic smooth muscle cells as well as in primary human hepatocytes, whereas neither IκB-kinase activity nor the degradation rate of IκBα were affected. Using PPARα-null mice, we demonstrated that Fibrates induced IκBα in liver in vivo and that this action required PPARα. Furthermore, fibrate treatment induced IκBα protein expression in the cytoplasm and also enhanced IL-1β-induced accumulation of IκBα protein in the nucleus. These actions of Fibrates on IκBα expression were accompanied by a decrease in NF-κB DNA binding activity as demonstrated by electrophoretic mobility shift assays. Taken together, these data provide an additional molecular mechanism for the anti-inflammatory activity of PPARα agonists and reinforce their potential use in the treatment of inflammatory diseases.
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regulation of lipid and lipoprotein metabolism by ppar activators
Clinical Chemistry and Laboratory Medicine, 2000Co-Authors: Philippe Gervois, J C Fruchart, Ines Pineda Torra, Bart StaelsAbstract:The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPAR alpha, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and muscle. PPAR gamma, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by pharmacological drugs, such as Fibrates for PPAR alpha and glitazones for PPAR gamma. PPAR alpha mediates the hypolipidemic action of Fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPAR alpha is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPAR alpha down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPAR alpha activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPAR gamma-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better understanding of the mechanism of action of Fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs.
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peroxisome proliferator activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross talk with transcription factors nf kappab and ap 1
Journal of Biological Chemistry, 1999Co-Authors: Philippe Delerive, Jean-charles Fruchart, Karolien De Bosscher, Sandrine Besnard, Wim Vanden Berghe, Jeffrey M Peters, Frank J Gonzalez, Alain Tedgui, Guy Haegeman, Bart StaelsAbstract:Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPARalpha) ligands (Fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARalpha-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARalpha wild-type, but not of PPARalpha-null mice, demonstrating a role for PPARalpha in this fibrate action. In human aortic SMC, Fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARalpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARalpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARalpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARalpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARalpha-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARalpha physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that Fibrates inhibit the vascular inflammatory response via PPARalpha by interfering with the NF-kappaB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.
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peroxisome proliferator activated receptor α negatively regulates the vascular inflammatory gene response by negative cross talk with transcription factors nf κb and ap 1
Journal of Biological Chemistry, 1999Co-Authors: Philippe Delerive, Jean-charles Fruchart, Karolien De Bosscher, Sandrine Besnard, Wim Vanden Berghe, Jeffrey M Peters, Frank J Gonzalez, Alain Tedgui, Guy Haegeman, Bart StaelsAbstract:Abstract Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor α (PPARα) ligands (Fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARα-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARα wild-type, but not of PPARα-null mice, demonstrating a role for PPARα in this fibrate action. In human aortic SMC, Fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARα represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARα and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARα-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARα, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARα-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARα physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that Fibrates inhibit the vascular inflammatory response via PPARα by interfering with the NF-κB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.
Hans M.g. Princen - One of the best experts on this subject based on the ideXlab platform.
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Fibrates suppress bile acid synthesis via peroxisome proliferator activated receptor α mediated downregulation of cholesterol 7α hydroxylase and sterol 27 hydroxylase expression
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: S M Post, Bart Staels, Helene Duez, Philippe Gervois, Folkert Kuipers, Hans M.g. PrincenAbstract:Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of Fibrates on bile acid synthesis. Ciprofibrate and the PPARalpha agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7alpha-hydroxylase enzyme activity and mRNA. The functional involvement of PPARalpha in the suppression of both enzymes was proven with the use of PPARalpha-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARalpha-null mice. A decreased bile acid production by PPARalpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
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Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator activated receptor α
Blood, 1999Co-Authors: Maaike Kockx, Hans M.g. Princen, Philippe Gervois, Jeffrey M Peters, Frank J Gonzalez, Philippe Poulain, Bruno Derudas, Teake Kooistra, Bart StaelsAbstract: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 Aα-, Bβ-, and γ-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 Aα-chain. Other Fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of Fibrates is specific for peroxisome proliferator-activated receptor-α (PPARα) because a high- affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPARα in the suppression of fibrinogen by Fibrates was obtained using PPARα-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 Aα-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 Aα-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPARα regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPARα.
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fibrate modulated expression of fibrinogen plasminogen activator inhibitor 1 and apolipoprotein a i in cultured cynomolgus monkey hepatocytes role of the peroxisome proliferator activated receptor α
Thrombosis and Haemostasis, 1998Co-Authors: Maaike Kockx, Hans M.g. Princen, Teake KooistraAbstract:Fibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, Fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of Fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes. We show that Fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different Fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα transactivation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p < 0.01) between PPARα transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARα transactivation activity (r = 0.47; p = 0.24), whereas such a correlation was absent for PAI-1 (r = 0.03; p = 0.95). These results strongly suggest an involvement of PPARα in the regulation of fibrinogen gene expression.
Philippe Costet - One of the best experts on this subject based on the ideXlab platform.
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dual mechanisms for the fibrate mediated repression of proprotein convertase subtilisin kexin type 9
Journal of Biological Chemistry, 2008Co-Authors: Sanae Kourimate, Bertrand Cariou, Cedric Le May, Cedric Langhi, M Krempf, Anne Laure Jarnoux, Khadija Ouguerram, Yassine Zair, Patrick Nguyen, Philippe CostetAbstract:Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPARα activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various Fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPARα-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, Fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARα activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.
Hayato Tada - One of the best experts on this subject based on the ideXlab platform.
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comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus results from a crossover study
Atherosclerosis, 2011Co-Authors: Tohru Noguchi, Junji Kobayashi, Kunimasa Yagi, Atsushi Nohara, Naoto Yamaaki, Masako Sugihara, Naoko Ito, Rie Oka, Masaaki Kawashiri, Hayato TadaAbstract:Abstract Background Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. Methods An open, randomized, four-phased crossover study using 400mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61±16 years, body mass index (BMI) 26±3kg/m 2 , total cholesterol (TC) 219±53mg/dL, triglyceride (TG) 183±83mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46±8mg/dL, fasting plasma glucose 133±31mg/dL and HbA1c 6.2±0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. Results Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p p vs. −32.9%, p p vs. +11.7%, p p p p p p p p Conclusion Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective Fibrates.