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Biomedical subjects

B Staels

Publications and source records attributed to B Staels.

At least 91 records · Page 5Linked to original sources
PubMed1999

Schistosoma mansoni schistosomula reduce E-selectin and VCAM-1 expression in TNF-alpha-stimulated lung microvascular endothelial cells by interfering with the NF-kappaB pathway.

The recruitment of immune cells into the lungs is a key step in protection against murine schistosomiasis. In this phenomenon, pulmonary (micro)vascular endothelial cells (EC) probably play a central role, by expressing specific adhesion molecules on their surface. Recently, we have shown that Schistosoma mansoni schistosomula, the parasitic stage which resides in the lungs, could activate microvascular EC to acquire an anti-inflammatory phenotype. In the present study, we tested the hypothesis that schistosomula could also regulate the expression of adhesion molecules in vitro by human lung microvascular EC (HMVEC-l) in the present of the pro-inflammatory cytokine TNF-alpha. We found that lipophilic substance(s) present in the excretory/secretory products from schistosomula selectively reduce the TNF-alpha-induced synthesis of E-selectin and VCAM-1 mRNA and proteins without affecting ICAM-1. This inhibitory effect appears to be mediated by a cyclic AMP/protein kinase A (cAMP/PKA) pathway that probably interferes with the NF-kappaB pathway induced by TNF-alpha at the level of the E-selectin promoter, whereas a cAMP-independent pathway appears to operate in VCAM-1 down-modulation. Finally, schistosomula also significantly reduce the VLA-4/VCAM-1-dependent adherence of leukocytes to TNF-alpha-stimulated HMVEC-l. We speculate that this mechanism could represent a new stratagem that parasites may use to escape the immune system by controlling leukocyte recruitment to the lungs.

Animals↗
PubMed1999

Effects of Pinus pinaster and Pinus koraiensis seed oil supplementation on lipoprotein metabolism in the rat.

The aim of the present study was to assess the effect of vegetal oils obtained from Pinus pinaster and P. koraiensis seeds on plasma lipoprotein levels and apolipoprotein (apo) gene expression in rats. These oils contain two particular fatty acids of the delta5-unsaturated polymethylene-interrupted fatty acid (delta5-UPIFA) family: all-cis-5,9,12-1 8:3 (pinolenic) and/or all-cis-5,11,14-20:3 (sciadonic) acids. Rats were fed for 28 d a diet containing 5% (w/w) oil supplement. Two control diets were prepared to match the fatty acid composition of P. pinaster or P. koraiensis oils with the exception of delta5-UPIFA, which were replaced by oleic acid. Pinus pinaster seed oil decreased serum triglycerides by 30% (P < 0.02), very low density lipoprotein (VLDL)-triglycerides by 40% (P < 0.01), and VLDL-cholesterol by 33% (P < 0.03). Pinus koraiensis seed oil decreased serum triglycerides by 16% [not statistically significant (ns)] and VLDL-triglycerides by 21% (ns). Gel permeation chromatography and nondenaturating polyacrylamide gel electrophoresis showed a tendency of high density lipoprotein to shift toward larger particles in pine seed oil-supplemented rats. Finally, P. pinaster seed oil treatment was associated with a small decrease of liver apoC-III (P < 0.02) but not in apoE, apoA-I, or apoA-II mRNA levels. The levels of circulating apo were not affected by pine seed oil supplementation. In conclusion, P. pinaster seed oil has a triglyceride-lowering effect in rats, an effect that is due to a reduction in circulating VLDL.

Animals↗
PubMed1999

Comparison of expression and regulation of the high-density lipoprotein receptor SR-BI and the low-density lipoprotein receptor in human adrenocortical carcinoma NCI-H295 cells.

In rodents, cholesterol for adrenal steroidogenesis is derived mainly from high-density lipoproteins (HDL) via the HDL receptor, scavenger receptor-BI (SR-BI). In humans cholesterol for steroidogenesis is considered to be derived from the low-density lipoprotein (LDL) receptor pathway, and the contribution of SR-BI to that is unknown. In the present study SR-BI expression and regulation by steroidogenic stimuli was analysed in human adrenocortical cells and compared with LDL receptor expression. In addition, the functional contribution of both receptors for cholesteryl ester delivery to human adrenocortical cells was compared. Northern blot and reverse transcription-PCR amplification and sequence analysis demonstrated the presence of SR-BI mRNA in foetal and adult human adrenal cortex. Furthermore, SR-BI mRNA was expressed to similar levels in human primary adrenocortical and adrenocortical carcinoma NCI-H295 cells, indicating its presence in the steroid-producing cells. Treatment of NCI-H295 cells with 8Br-cAMP, a stimulator of glucocorticoid synthesis via the protein kinase A second messenger signal transduction pathway, resulted in an increase of both SR-BI and LDL receptor mRNA levels in a time- and dose-dependent manner. The induction of SR-BI and LDL receptor by cAMP was independent of ongoing protein synthesis and occurred at the transcriptional level. Ligand blot experiments indicated that a protein of similar size to SR-BI is the major HDL-binding protein in NCI-H295 cells. Western blot analysis demonstrated that cAMP treatment increased the levels of LDL receptor and, to a lesser extent, SR-BI protein in NCI-H295 cells. Binding and uptake of cholesterol was quantitatively smaller from HDL than from LDL, both in basal as well as in cAMP-stimulated cells. Scatchard analysis under basal conditions indicated that NCI-H295 cells express twice as many specific binding sites for LDL than for HDL. Dissociation constant values (Kd; in nm) were approximately five times higher for HDL than for LDL, indicating a lower affinity of HDL compared with LDL. The combined effects of these two parameters and the low cholesteryl ester content of HDL subfraction 3 (HDL3) contributes to a lower cholesteryl ester uptake from HDL than from LDL by the NCI-H295 cells. In conclusion, both the SR-BI and LDL receptor genes are expressed in the human adrenal cortex and coordinately regulated by activators of glucocorticoid synthesis. In contrast to rodents, in human adrenocortical cells the HDL pathway of cholesterol delivery appears to be of lesser importance than the LDL pathway. Nevertheless, the SR-BI pathway may become of major importance in conditions of functional defects in the LDL receptor pathway.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPAR alpha form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPAR alpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. It is likely that these actions of PPAR alpha activators on lipid, glucose and energy metabolism are, at least in part, due to the increase of hepatic fatty acid beta-oxidation resulting in an enhanced fatty acid flux and degradation in the liver. Moreover, PPARs are expressed in different immunological and vascular wall cell types where they exert anti-inflammatory and proapoptotic activities. The observation that these receptors are also expressed in atherosclerotic lesions suggests a role in atherogenesis. Finally, PPAR alpha activators correct age-related dysregulations in redox balance. Taken together, these data indicate a modulatory role for PPAR alpha in the pathogenesis of age-related disorders, such as dyslipidemia, insulin resistance and chronic inflammation, predisposing to atherosclerosis.

Aging↗
PubMed1999

Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.

Animals↗
PubMed1999

Cell culture conditions determine apolipoprotein CIII secretion and regulation by fibrates in human hepatoma HepG2 cells.

Fibrates are widely used drugs which lower triglycerides and increase HDL concentrations in serum. Recent findings from our laboratory have shown that fibrates repress apolipoprotein (apo) CIII gene expression, an effect that explains partially the triglyceride-lowering activity of these drugs. The goal of the present study was to compare the effect of various fibrates on apo CIII gene expression in the human hepatoblastoma cell line HepG2. First, we demonstrate that the level of apo CIII secretion by HepG2 cells is controlled by serum factors whereas apo CIII mRNA levels are not and even increase under conditions when apo CIII secretion dramatically decreases. Twelve different fetal calf serum batches were tested during this study and apo CIII secretion in cell medium could only be detected with three of them. The effect of serum on apolipoprotein secretion was more pronounced for apo CIII whereas other apolipoproteins (apo E, apo B, apo AII and apo AI) were affected to a lesser extent. Under serum conditions allowing apo CIII secretion, treatment with the peroxisome-proliferator activated receptor (PPAR)alpha activators fenofibrate, gemfibrozil and Wy-14643 result in a marked lowering of apo CIII secretion and gene expression, this effect being most pronounced with Wy-14643. Comparison of the activity of a PPARgamma-specific ligand, the antidiabetic thiazolidinedione, BRL-49653 and a PPARalpha ligand Wy-14643 showed a marked decrease of apo CIII secretion and gene expression after activation of PPARalpha but not PPARgamma. In conclusion, fibrates down-regulate apo CIII gene expression in human HepG2 cells, most likely via PPARalpha but not via PPARgamma. However, these effects are only observed in HepG2 cells cultured under appropriate conditions.

Animals↗
PubMed1999

Developmental and pharmacological regulation of apolipoprotein C-II gene expression. Comparison with apo C-I and apo C-III gene regulation.

Increased plasma triglyceride concentrations are often observed in metabolic disorders predisposing to coronary heart disease. Among the major determinants of plasma triglyceride metabolism are the apolipoproteins (apos) of the C class, C-I, C-II, and C-III. Whereas physiological concentrations of apo C-II are required for lipolysis of triglycerides by lipoprotein lipase (LPL), overexpression of all 3 C apolipoproteins leads to hypertriglyceridemia. In the present study, we investigated apo C-II gene regulation under conditions associated with profound changes in plasma triglyceride metabolism, ie, during postnatal development and after treatment with the triglyceride-lowering fibrate drugs, and compared its expression to that of apo C-I and apo C-III. Whereas the expression of both apo C-I and apo C-III is low in fetal liver, increases gradually after birth, and attains maximal levels after weaning, apo C-II gene expression is already detectable in the fetal liver, increases rapidly immediately after birth, and remains elevated throughout suckling. Thus, the increased ingestion of lipids during suckling is met by an earlier induction of apo C-II, the obligatory activator for LPL, compared with apo C-III and apo C-I, which antagonize triglyceride catabolism. Treatment of rats with fibrates decreased apo C-II gene expression in the liver, but not in the intestine, whereas apo C-I gene expression did not change. The decrease of liver apo C-II mRNA levels after fenofibrate occurred in a time- and dose-dependent manner and was reversible but appeared less pronounced than the decrease of apo C-III mRNA. Apo C-II mRNA levels were not affected after treatment with BRL49653, a peroxisome proliferator-activated receptor (PPAR)gamma-specific ligand, suggesting that fibrates act on apo C-II expression via PPARalpha. Addition of fenofibric acid to primary rat and human hepatocytes resulted in a decrease of apo C-II expression. In conclusion, fibrates decrease gene expression of apo C-II and apo C-III, but not apo C-I, in rat and human hepatocytes. This decrease of apo C-II and apo C-III gene expression, together with a lowered apo C-III to apo C-II ratio, should result in an improved clearance of triglyceride-rich remnant lipoproteins from plasma, without hampering triglyceride lipolysis by LPL.

Aging↗
PubMed1999

Fibrates increase human REV-ERBalpha expression in liver via a novel peroxisome proliferator-activated receptor response element.

Fibrates are widely used hypolipidemic drugs that act by modulating the expression of genes involved in lipid and lipoprotein metabolism. Whereas the activation of gene transcription by fibrates occurs via the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) interacting with response elements consisting of a direct repeat of the AGGTCA motif spaced by one nucleotide (DR1), the mechanisms of negative gene regulation by fibrates and PPARalpha are largely unknown. In the present study, we demonstrate that fibrates induce the expression of the nuclear receptor Rev-erbalpha, a negative regulator of gene transcription. Fibrates increase Rev-erbalpha mRNA levels both in primary human hepatocytes and in HepG2 hepatoblastoma cells. In HepG2 cells, fibrates furthermore induce Rev-erbalpha protein synthesis rates. Transfection studies with reporter constructs driven by the human Rev-erbalpha promoter revealed that fibrates induce Rev-erbalpha expression at the transcriptional level via PPARalpha. Site-directed mutagenesis experiments identified a PPAR response element that coincides with the previously identified Rev-erbalpha negative autoregulatory Rev-DR2 element. Electromobility shift assay experiments indicated that PPARalpha binds as heterodimer with 9-cis-retinoic acid receptor to a subset of DR2 elements 5' flanked by an A/T-rich sequence such as in the Rev-DR2. PPARalpha and Rev-erbalpha bind with similar affinities to the Rev-DR2 site. In conclusion, these data demonstrate human Rev-erbalpha as a PPARalpha target gene and identify a subset of DR2 sites as novel PPARalpha response elements. Finally, the PPARalpha and Rev-erbalpha signaling pathways cross-talk through competition for binding to those response elements.

Binding Sites↗
PubMed1999

A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity.

The peroxisome proliferator-activated receptor alpha (PPARalpha) plays a key role in lipid and lipoprotein metabolism. However, important inter- and intraspecies differences exist in the response to PPARalpha activators. This incited us to screen for PPARalpha variants with different signaling functions. In the present study, using a RT-PCR approach a variant human PPARalpha mRNA species was identified, which lacks the entire exon 6 due to alternative splicing. This deletion leads to the introduction of a premature stop codon, resulting in the formation of a truncated PPARalpha protein (PPARalphatr) lacking part of the hinge region and the entire ligand-binding domain. RNase protection analysis demonstrated that PPARalphatr mRNA is expressed in several human tissues and cells, representing between 20-50% of total PPARalpha mRNA. By contrast, PPARalphatr mRNA could not be detected in rodent tissues. Western blot analysis using PPARalpha-specific antibodies demonstrated the presence of an immunoreactive protein migrating at the size of in vitro produced PPARalphatr protein both in human hepatoma HepG2 cells and in human hepatocytes. Both in the presence or absence of 9-cis-retinoic acid receptor, PPARalphatr did not bind to DNA in gel shift assays. Immunocytochemical analysis of transfected CV-1 cells indicated that, whereas transfected PPARalphawt was mainly nuclear localized, the majority of PPARalphatr resided in the cytoplasm, with presence in the nucleus depending on cell culture conditions. Whereas a chimeric PPARalphatr protein containing a nuclear localization signal cloned at its N-terminal localized into the nucleus and exhibited strong negative activity on PPARalphawt transactivation function, PPARalphatr interfered with PPARalphatr transactivation function only under culture conditions inducing its nuclear localization. Cotransfection of the coactivator CREB-binding protein relieved the transcriptional repression of PPARalphawt by PPARalphatr, suggesting that the dominant negative effect of PPARalphatr might occur through competition for essential coactivators. In addition, PPARalphatr interfered with transcriptional activity of other nuclear receptors such as PPARgamma, hepatic nuclear factor-4, and glucocorticoid receptor-alpha, which share CREB-binding protein/p300 as a coactivator. Thus, we have identified a human PPARalpha splice variant that may negatively interfere with PPARalphawt function. Factors regulating either the ratio of PPARalphawt vs. PPARalphatr mRNA or the nuclear entry of PPARalphatr protein should therefore lead to altered signaling via the PPARalpha and, possibly also, other nuclear receptor pathways.

Animals↗
PubMed1999

Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.

3-Thia fatty acids are modified fatty acids that promote hepatic peroxisome proliferation and decrease serum triacylglycerol, cholesterol and free fatty acid levels in rats. In vivo administration of tetradecylthioacetic acid (TTA) to rats led to a significant decrease in liver apolipoproteins apoA-I, A-II, A-IV, and C-III mRNA levels, and to an increase of liver acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-II, and 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-CoA synthase) mRNA levels and activities. By contrast, no significant changes of lipoprotein lipase (LPL) mRNA levels were detected in rat epididymal adipose tissue. Liver carnitine palmitoyltransferase-I, apoB, apoE, and LDL receptor mRNA levels were not significantly affected. When tested in vitro, TTA increased rat ACO and carnitine palmitoyltransferase-I mRNA levels in primary rat hepatocytes and also LPL mRNA levels in 3T3-L1 preadipocytes. TTA also enhanced the transcriptional activity of chimeras containing the DNA binding domain of the yeast transcription factor Gal4 fused to the ligand binding domain of either human PPARalpha or human PPARgamma. The effect depended on the concentration tested and the cell type. In conclusion, our data suggest that in vitro, TTA activates both PPARalpha and PPARgamma, but the latter with much lower affinity. TTA affects serum lipid levels in vivo in rats by acting mainly on the liver via PPARalpha where it decreases the liver expression of genes involved in vascular lipid transport and increases the expression of genes involved in intracellular fatty acid metabolism. -Raspé, E., L. Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe, J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.

3T3 Cells↗
PubMed1999

[Molecular mechanism of action of the fibrates].

Fibrates are old hypolipidemic drugs with pleitropic effects on lipid metabolism. Until, recently their intimate molecular mechanisms of action were mysterious. In the late 5 years, we have shown that the pharmacological effects of fibrates depend on their binding to "Peroxisome Proliferator Activated Receptor alpha" (PPAR alpha). The binding of fibrates to PPAR alpha induces the activation or the inhibition of multiple genes involved in lipid metabolism through the binding of the activated PPAR alpha to "Peroxisome Proliferator Response Element" (PPRE) located in the gene promoters. Fibrates reduce plasma triglyceride levels by altering the expression of numerous genes coding for proteins involved in fatty acid metabolism (fatty acid transport protein, acyl-CoA synthetase, etc.) and also by increasing the lipoprotein lipase synthesis and decreasing the apolipoprotein C-III synthesis. Fibrates increase HDL cholesterol levels by increasing apolipoprotein A-I and apolipoprotein A-II synthesis. Furthermore, we recently demonstrated that fibrates are potent anti-inflammatory molecules through an indirect modulation of the nuclear-factor-kappa B activity. Therefore, we suggest that fibrates inhibit atherosclerosis development not only by improving the plasma lipid profile but also by reducing inflammation in the vascular wall.

Animals↗
PubMed1998

Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha.

BACKGROUND: Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown. METHODS AND RESULTS: We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in sg/sg mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected. CONCLUSIONS: These results suggest that the RORalpha gene contributes to the plasma HDL level and susceptibility to atherosclerosis.

Animals↗
PubMed1998

Mechanism of action of fibrates on lipid and lipoprotein metabolism.

Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-alpha form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase--mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the beta-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression.

Humans↗
PubMed1998

Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPARalpha and PPARgamma forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARalpha is already present in undifferentiated monocytes, PPARgamma expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARalpha resides constitutively in the cytoplasm, whereas PPARgamma is predominantly nuclear localized. Transient transfection experiments indicate that PPARalpha and PPARgamma are transcriptionally active after ligand stimulation. Ligand activation of PPARgamma, but not of PPARalpha, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPARalpha and PPARgamma ligands induce apoptosis of macrophages activated with tumor necrosis factor alpha/interferon gamma. Finally, PPARgamma inhibits the transcriptional activity of the NFkappaB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFkappaB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.

Apoptosis↗
PubMed1998

The nuclear receptors peroxisome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates.

Fibrates are widely used hypolipidemic drugs which activate the nuclear peroxisome proliferator-activated receptor (PPAR) alpha and thereby alter the transcription of genes controlling lipoprotein metabolism. Fibrates influence plasma high density lipoprotein and its major protein, apolipoprotein (apo) A-I, in an opposite manner in man (increase) versus rodents (decrease). In the present study we studied the molecular mechanisms of this species-specific regulation of apoA-I expression by fibrates. In primary rat and human hepatocytes fenofibric acid, respectively, decreased and increased apoA-I mRNA levels. The absence of induction of rat apoA-I gene expression by fibrates is due to 3 nucleotide differences between the rat and the human apoA-I promoter A site, rendering a positive PPAR-response element in the human apoA-I promoter nonfunctional in rats. In contrast, rat, but not human, apoA-I transcription is repressed by the nuclear receptor Rev-erbalpha, which binds to a negative response element adjacent to the TATA box of the rat apoA-I promoter. In rats fibrates increase liver Rev-erbalpha mRNA levels >10-fold. In conclusion, the opposite regulation of rat and human apoA-I gene expression by fibrates is linked to differences in cis-elements in their respective promoters leading to repression by Rev-erbalpha of rat apoA-I and activation by PPARalpha of human apoA-I. Finally, Rev-erbalpha is identified as a novel fibrate target gene, suggesting a role for this nuclear receptor in lipid and lipoprotein metabolism.

Animals↗