Biomedical subjects

Jean-Charles Fruchart

Publications and source records attributed to Jean-Charles Fruchart.

At least 73 records · Page 4Linked to original sources

PubMed2004

Measurement of arterial wall thickness as a surrogate marker for atherosclerosis.

Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls.

Adolescent↗

PubMed2004

The farnesoid X receptor induces very low density lipoprotein receptor gene expression.

The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). In response to ligand-binding, FXR regulates many genes involved in BA, lipid, and lipoprotein metabolism. To identify new FXR target genes, microarray technology was used to profile total RNA extracted from HepG2 cells treated with the natural FXR agonist chenodeoxycholic acid (CDCA). Interestingly, a significant increase of transcript level of the very low density lipoprotein receptor (VLDLR) was observed. Our data, resulting from selective FXR activation, FXR RNA silencing and FXR-deficient mice, clearly demonstrate that BAs up-regulate VLDLR transcript levels via a FXR-dependent mechanism in vitro in human and in vivo in mouse liver cells.

Animals↗

PubMed2004

Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.

A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and beta/delta as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARalpha, gamma, and beta/delta subtypes are approximately 60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARalpha is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARalpha controls expression of genes implicated in lipid metabolism. PPARgamma, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARgamma include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyDelta12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARbeta/delta are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARbeta/delta stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARalpha and PPARgamma activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARbeta/delta agonists on atherogenesis. Given the widespread use of PPARalpha and PPARgamma agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.

Animals↗

PubMed2004

The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha.

Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor implicated in several physiological processes such as lipid and lipoprotein metabolism, glucose homeostasis, and the inflammatory response. PPARalpha is activated by natural fatty acids and synthetic compounds like fibrates. PPARalpha activity has been shown to be modulated by its phosphorylation status. PPARalpha is phosphorylated by kinases such as the MAPKs and cAMP-activated protein kinase A. In this report, we show that protein kinase C (PKC) inhibition impairs ligand-activated PPARalpha transcriptional activity. Furthermore, PKC inhibition decreases PPARalpha ligand-induction of its target genes including PPARalpha itself and carnitine palmitoyltransferase I. By contrast, PKC inhibition enhances PPARalpha transrepression properties as demonstrated using the fibrinogen-beta gene as model system. Finally, PKC inhibition decreases PPARalpha phosphorylation activity of hepatocyte cell extracts. In addition, PPARalpha purified protein is phosphorylated in vitro by recombinant PKCalpha and betaII. The replacement of serines 179 and 230 by alanine residues reduces the phosphorylation of the PPARalpha protein. The PPARalpha S179A-S230A protein displays an impaired ligand-induced transactivation activity and an enhanced trans-repression activity. Altogether, our data indicate that the PKC signaling pathway acts as a molecular switch dissociating the transactivation and transrepression functions of PPARalpha, which involved phosphorylation of serines 179 and 230.

Alanine↗

PubMed2004

Analysis of apolipoprotein A5, c3, and plasma triglyceride concentrations in genetically engineered mice.

OBJECTIVE: Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides. METHODS AND RESULTS: To address this issue, we generated independent lines of mice that either overexpressed ("double transgenic") or completely lacked ("double knockout") both apolipoprotein genes. We report that both "double transgenic" and "double knockout" mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the "double transgenic" mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration. CONCLUSIONS: Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner.

Animals↗

PubMed2004

Expression and secretion of human apolipoprotein A-I in the heart.

Various studies have correlated apolipoprotein (apo) A-I, the major component high-density lipoprotein, with protection against development of cardiovascular disease. Although apoA-I expression has been previously detected in the liver and intestine, we have discovered that the human apoA-I gene is also expressed in the heart. Using transgenic (Tg) mice generated with the human apoA-I/C-III/A-IV gene cluster and Tg mice produced with just the 2.2 kb human apoA-I gene, we have detected significant levels of apoA-I expression in the heart. Furthermore, the detection of apoA-I expression in the hearts of human apoA-I Tg mice indicates that the minimal regulatory elements necessary for cardiac expression of the gene are located near its coding sequence. To determine if the apoA-I gene is also expressed in the human heart, similar analyses were performed, where apoA-I expression was found in both adult and fetal hearts. Furthermore in-depth investigation of the various regions of human and Tg mouse hearts revealed that the apoA-I mRNA was present in the ventricles and atria, but not in the aorta. In situ hybridization of Tg mouse hearts revealed that apoA-I expression was restricted to the cardiac myocyte cells. Finally, heart explants and cardiac primary culture experiments with Tg mice showed secretion of particles containing the human apoA-I protein, and metabolic labeling experiments have also detected a 28 kDa human apoA-I protein secreted from the heart. From these novel findings, new insights into the role and function of apoA-I can be extrapolated.

Animals↗

PubMed2004

Adipophilin enhances lipid accumulation and prevents lipid efflux from THP-1 macrophages: potential role in atherogenesis.

OBJECTIVE: Uptake of modified low-density lipoprotein (LDL) by macrophages through scavenger receptors results in lipid droplets accumulation and foam cell formation. Excess lipid deposition in macrophages has been reported to modulate expression of several genes including adipophilin. In this study, we investigated the function of adipophilin in lipid accumulation and cholesterol efflux in THP-1 macrophages. METHODS AND RESULTS: Adipophilin mRNA expression was 3.5-fold higher in human atherosclerotic plaques compared with healthy areas of the same arteries. Moreover, in the presence of acetylated LDL (AcLDL), triglycerides and cholesteryl esters were increased in macrophages overexpressing adipophilin by 40% and 67%, respectively, whereas their accumulation was reduced when endogenous cellular adipophilin was depleted using siRNA approach. In addition, neither overexpression nor downregulation of adipophilin altered expression of genes involved in lipid efflux. However, the affinity and the number of AcLDL receptors were not affected. After 24-hour incubation of lipid-loaded macrophages with apolipoprotein A-I, cholesterol efflux was reduced by 47% in adipophilin transfected cells versus control cells. CONCLUSIONS: Our results showed that stimulation of adipophilin expression in macrophages by modified LDL promotes triglycerides and cholesterol storage and reduces cholesterol efflux. Therefore, adipophilin might contribute, in vivo, to lipid accumulation in the intima of the arterial wall.

Apolipoprotein A-I↗

PubMed2004

The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia.

BACKGROUND: Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. The role of CETP in atherogenesis is controversial. To better understand the relationships between plasma CETP levels, lipoproteins and atherosclerosis, we assessed these parameters in patients with an enhanced risk for atherosclerosis. METHODS AND RESULTS: We investigated 281 patients with familial hypercholesterolemia (FH) in which the effects of two statins were compared in a 2-year, randomized, double-blinded study. Patients were stratified in quartiles according to their CETP baseline levels. In addition to correlations with decreased high-density lipoprotein cholesterol (HDL-c), increased low-density lipoprotein cholesterol (LDL-c) and enhanced triglyceride levels, higher CETP levels were also associated with reduced HDL particle size, and smaller and denser LDL. Statins reduced plasma CETP levels and atherogenic lipoproteins. Nevertheless, baseline CETP concentration was positively associated with IMT after 2 years of therapy. CONCLUSION: This study provides evidence that CETP levels are associated with a more atherogenic lipid profile and increased progression of atherosclerosis. Statin treatment improved the lipoprotein profile in FH patients, but to a lesser extent in those with high CETP levels. These findings might imply that statin treatment does not entirely counteract the lipoprotein abnormalities associated with high CETP levels.

Administration, Oral↗

PubMed2004

Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC(50) of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 microM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6)M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.

Arteriosclerosis↗

PubMed2004

Enhanced cholesterol efflux promotion in well-trained soccer players.

It is widely accepted that aerobic physical activity is associated with a less atherogenic lipid and lipoprotein profile and, consequently, with a reduced cardiovascular risk. Both cross-sectional studies and prospective-interventional trials show that the most frequent modification observed consists of a slight but significant increase in high-density lipoprotein cholesterol (HDL-C) levels. Nevertheless, only few studies made an attempt to elucidate if this quantitative modification was accompanied by an improvement in any of HDL antiatherogenic functions. The purpose of this study was to evaluate the main steps of reverse cholesterol transport, the best known antiatherogenic function performed by HDL, in a group of well-trained soccer players (n = 35) in comparison to sedentary controls (n = 15). Average HDL-C levels were 12.5% higher in the sportsmen, in large part because of greater HDL2-C concentration. No statistically significant differences were observed in the other lipid- and lipoprotein-related parameters. The capacity to promote cholesterol efflux from Fu5AH cells was significantly higher in the soccer players than in the control individuals (20.5% +/- 0.4% v 15.9% +/- 1.2%, respectively, P < .001). However, lecithin:cholesterol acyltransferase (LCAT; 2.6 +/- 0.9 v 1.4 +/- 0.3%/mL.h, respectively) and cholesteryl ester transfer protein (CETP; 69.5 +/- 8.3 v 62.7 +/- 14.8%/mL.h, respectively) activities did not reach statistically significant difference between both groups. Correlation analysis showed that cholesterol efflux induced by serum samples was directly related to HDL-C (r = 0.59, P < .001), HDL2-C (r = 0.37, P < .01), and lipoprotein (Lp)A-I (r = 0.44, P < .05). On the other hand, negative correlations were observed with waist/hip ratio (r = -0.36, P < .05), low-density lipoprotein cholesterol (LDL-C; r = -0.33, P < .05), apolipoprotein B (apo B; r = -0.42, P < .05), and LpA-I;A-II (r = -0.51, P < .005). In conclusion, the well-known cardioprotective benefit of regular exercise could be based, at least in part, on a less atherogenic lipid and lipoprotein profile and an enhanced cellular cholesterol efflux.

Adolescent↗

PubMed2004

Genomic and non-genomic interactions of PPARalpha with xenobiotic-metabolizing enzymes.

The hypolipidemic properties of fibrates, synthetic activators of the nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), have been studied extensively. Recent observations indicate, however, that PPARalpha also functions as a regulator of endobiotic and xenobiotic metabolism in rodents and humans. Activators of PPARalpha affect xenobiotic-metabolizing enzymes (XMEs) at different levels. At the genomic level, the expression of numerous cytochrome P450 (CYP) and phase II conjugating genes is altered in a species-distinct manner on treatment with PPARalpha activators. As a result of such regulatory processes, PPARalpha affects the homeostasis of both its own natural ligands and other compounds including bile acids. At the non-genomic level, PPARalpha activators can act as competitive inhibitors for inactivating other molecules, leading to drug-drug interactions. These global effects of PPARalpha activators on the activity of XMEs are of physiological and pharmaceutical importance, and demonstrate that thorough studies of the actions on XMEs of each novel PPARalpha agonist are warranted.

Animals↗

PubMed2004

Fenofibrate increases homocystinemia through a PPARalpha-mediated mechanism.

Plasma homocysteine levels increase in humans treated with fibrates but the molecular mechanisms are unknown. The goal of the present study was to determine the mechanism of this increase using animal models. Firstly, an increase in homocysteine was observed in mice treated with fenofibrate irrespective of the genetic background C57BL/6 or SV129. Secondly, as the effect of fenofibrate on gene expression is mediated through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), a transcription factor belonging to the nuclear receptor family, it was determined whether the effect of fenofibrate on homocysteine levels were modulated through PPARalpha activation. Using PPARalpha-deficient mice, it was shown that the homocysteine increase after fenofibrate treatment was completely abolished in these animals. It can be concluded that fibrates increase homocystinemia through a PPARalpha-mediated mechanism and that mice constitute an animal model for analyzing the molecular mechanisms behind the homocysteine increase after fibrate therapy in dyslipidemic patients.

Animals↗

PubMed2004

Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe.

OBJECTIVE: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia. RESEARCH DESIGN AND METHODS: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C > or = 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14. MAIN OUTCOME MEASURES: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate. RESULTS: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (p < or = 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (p < or = 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (p < or = 0.05 vs placebo), and LDL-III (p < or = 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C(max) and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant. CONCLUSION: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.

Adult↗

PubMed2004

Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C.

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of CHD due to low HDL-C. Based on the available evidence, the European Consensus Panel recommends that the minimum target for HDL-C should be 40 mg/dL (1.03 mmol/L) in patients with CHD or with a high level of risk for CHD, including patients at high global risk with type 2 diabetes or the metabolic syndrome.

Cholesterol, HDL↗

PubMed2004

Natural phenylpropanoids inhibit lipoprotein-induced endothelin-1 secretion by endothelial cells.

There is increasing evidence that oxidized low-density lipoproteins (Ox-LDL) might be involved in the pathogenesis of atherosclerosis and it has been reported that polyphenols inhibit LDL peroxidation and atherosclerosis. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide isolated from endothelial cells and it induces smooth muscle cell proliferation. ET-1 secretion is increased in atheroma and induces deleterious effects such as vasospasm and atherosclerosis. The goal of this study was to test the effect of four natural phenolic compounds against copper-oxidized LDL (Cu-LDL)-induced ET-1 liberation by bovine aortic endothelial cells (BAEC). The tested compounds were phenylpropanoid glycosides previously isolated from the aerial parts of Marrubium vulgare L. (acteoside 1, forsythoside B 2, arenarioside 3 and ballotetroside 4). ET-1 secretion increased when cells were incubated with Cu-LDL but the compounds 1-4 inhibited this increase. These results were confirmed by quantitative-polymerase chain reaction (QPCR) analysis. Since ET-1 plays an important role in atherosclerosis development, our work suggests that the tested phenylpropanoids could have a beneficial effect in inhibiting atherosclerosis development.

Animals↗

PubMed2004

Glucose regulates the expression of the farnesoid X receptor in liver.

An increased prevalence of hypertriglyceridemia and gallbladder disease occurs in patients with diabetes or insulin resistance. Hypertriglyceridemia is positively associated to gall bladder disease risk. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays a key role in bile acid and triglyceride homeostasis. The mechanisms controlling FXR gene expression are poorly understood. This study evaluated whether FXR gene expression is regulated by alterations in glucose homeostasis. FXR expression was decreased in livers of streptozotocin-induced diabetic rats and normalized upon insulin supplementation. Concomitantly with diabetes progression, FXR expression also decreased in aging diabetic Zucker rats. In primary rat hepatocytes, D-glucose increased FXR mRNA in a dose- and time-dependent manner, whereas insulin counteracted this effect. Addition of xylitol, a precursor of xylulose-5-phosphate, to primary rat hepatocytes increased FXR expression to a comparable level as D-glucose. Finally, expression of the FXR target genes, SHP and apolipoprotein C-III, were additively regulated by D-glucose and FXR ligands. This study demonstrates that FXR is decreased in animal models of diabetes. In addition, FXR is regulated by glucose likely via the pentose phosphate pathway. Dysregulation of FXR expression may contribute to alterations in lipid and bile acid metabolism in patients with diabetes or insulin resistance.

Animals↗

PubMed2003

Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment.

The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. A new therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-alpha) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-alpha-deficient mice, suggesting that PPAR-alpha activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-alpha could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-alpha activators could preventively decrease the severity of stroke in humans.

Animals↗

PubMed2003

The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation.

Rev-Erbalpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene. Rev-Erbalpha mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor gamma (PPARgamma) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erbalpha expression is induced by PPARgamma activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Furthermore, activated PPARgamma induces Rev-Erbalpha promoter activity by binding to the direct repeat (DR)-2 response element Rev-DR2. Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation.

Adipocytes↗