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Biomedical subjects

B Staels

Publications and source records attributed to B Staels.

At least 19 recordsLinked to original sources
PubMed2006

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients.

AIMS/HYPOTHESIS: Insulin resistance is thought to be central to the pathogenesis of diabetic dyslipidaemia. We hypothesised that improving insulin sensitivity would improve fasting and postprandial triglyceride metabolism in patients with type 2 diabetes. To this aim we studied fasting and postprandial lipaemia in type 2 diabetic patients before and after sensitisation to insulin with pioglitazone, compared with that observed in patients on an insulin-providing regime. METHODS: In a double-blind placebo-controlled protocol, 22 patients with type 2 diabetes were randomly allocated to receive either pioglitazone (45 mg/day) or glibenclamide (5 mg/day), for a 20-week period. Fasting and postprandial lipid metabolism were investigated at baseline and at the end of the treatment period. A group of non-diabetic subjects was also studied. RESULTS: Compared with glibenclamide treatment, pioglitazone treatment decreased fasting triglyceride, glucose and insulin levels and the homeostasis model assessment score of insulin resistance. Decreased fasting triglyceride after pioglitazone treatment was due to reduced VLDL triglyceride, particularly VLDL-2. Lipoprotein lipase activity was unchanged by pioglitazone treatment but hepatic lipase showed a significant decrease. Pioglitazone treatment lowered total postprandial triglyceride, as well as chylomicron- and chylomicron-remnant retinyl palmitate levels to normal. Glucose disposal improved but remained abnormal. CONCLUSIONS/INTERPRETATION: Insulin sensitisation with pioglitazone has major effects in restoring postprandial lipaemia to normal, while also correcting fasting hypertriglyceridaemia; both factors may have consequences for atherogenic risk in diabetes.

Blood Glucose↗
PubMed2006

Transcriptional regulation of macrophage cholesterol trafficking by PPARalpha and LXR.

PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages.

Animals↗
PubMed2006

PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases.

PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.

Brain↗
PubMed2006

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition.

Peroxisome proliferator-activated receptors (PPARalpha, PPARbeta/delta and PPARgamma) are a family of nuclear receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPARgamma, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPARgamma in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPARgamma. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other 'insulin sensitizer' molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.

Corpus Luteum↗
PubMed2005

Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages.

The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor alpha (PPARalpha), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARalpha and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARalpha ligands in human macrophages. Furthermore, PPARalpha activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPARalpha activators. These observations identify a novel regulatory role for PPARalpha in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport.

Biological Transport↗
PubMed2005

Liver X receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages.

Liver X receptors (LXRs) are nuclear receptors that regulate macrophage cholesterol efflux by inducing ATP-binding cassette transporter A1 (ABCA1) and ABCG1/ABCG4 gene expression. The Niemann-Pick C (NPC) proteins NPC1 and NPC2 are located in the late endosome, where they control cholesterol trafficking to the plasma membrane. The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant governing its availability for efflux to extracellular acceptors. Here we investigated the influence of LXR activation on intracellular cholesterol trafficking in primary human macrophages. Synthetic LXR activators increase the amount of free cholesterol in the plasma membrane by inducing NPC1 and NPC2 gene expression. Moreover, ABCA1-dependent cholesterol efflux induced by LXR activators was drastically decreased in the presence of progesterone, which blocks postlysosomal cholesterol trafficking, and reduced when NPC1 and NPC2 mRNA expression was depleted using small interfering RNA. The stimulation of cholesterol mobilization to the plasma membrane by LXRs led to a decrease in cholesteryl ester formation and Acyl-coenzyme A cholesterol acyltransferase-1 activity. These data indicate that LXR activation enhances cholesterol trafficking to the plasma membrane, where it becomes available for efflux, at the expense of esterification, thus contributing to the overall effects of LXR agonists in the control of macrophage cholesterol homeostasis.

ATP Binding Cassette Transporter 1↗
PubMed2005

Fibrates.

Atherosclerosis of the large arteries is the main origin of cerebro- and cardiovascular diseases, the leading causes of mortality and morbidity in industrialized countries. The pathophysiology of coronary and cerebrovascular atherosclerosis is multifactorial and complex. Fibrates are hypolipidemic drugs that lower progression of atherosclerotic lesions mainly through activation of the nuclear receptor peroxisome-proliferator activated receptor-alpha. In addition, fibrates exert pleiotropic and anti-inflammatory actions. In this chapter, we will focus on the different effects of fibrates impacting on the development of atherosclerosis.

Animals↗
PubMed2005

The role of the orphan nuclear receptor Rev-Erb alpha in adipocyte differentiation and function.

Lipid and carbohydrate homeostasis in higher organisms is governed by an integrated system that has a capacity to rapidly respond to metabolic changes. Numerous signals reciprocally convey information about body fat status from the periphery to central nervous system in the attempt to maintain body weight nearly stable throughout life. The role of adipocyte in energy homeostasis extends its function as a simple energy storage cell. Indeed, adipose tissue not only secretes fatty acids, but is also an active endocrine and paracrine organ due to the production of secreted proteins and lipid indicators collectively called adipokines. These observations have spurred interest in the identification of the transcriptional and other regulatory pathways of adipocyte differentiation. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) (NR1C3) and members of the CCAAT enhancer-binding protein (C/EBP) family are central mediators controlling adipocyte differentiation and function. Rev-erb alpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene. Rev-erb alpha acts as a negative regulator of transcription binding to the same response element than another orphan nuclear receptor, ROR alpha. Rev-erb alpha is highly expressed in adipose tissue, skeletal muscle, heart, liver and brain. Rev-erb alpha expression increases during adipocyte differentiation of 3T3-L1 cells and is induced by PPAR gamma activation in both 3T3-L1 cells in vitro and in rat adipose tissue in vivo via a direct repeat (DR2) in the Rev-erb alpha promoter. Ectopic expression of Rev-erb alpha potentiates the adipocyte differentiation in 3T3-L1 cells. Recent results in vascular smooth muscle cells (VSMCs) indicate that Rev-erb alpha also controls inflammation by regulating NF-kappa B responsive genes, such as IL-6 and COX-2. Future studies on a potential role of Rev-erb alpha on glucose homeostasis and/or inflammation control are thus warranted.

Adipocytes↗
PubMed2005

Therapeutical effects of PPAR agonists assessed by biomarker modulation.

The metabolic syndrome is defined as the clustering of cardiovascular risk factors, such as glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances and hypertension. Activators of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors pre-disposing to atherosclerosis. Fibrates are hypolipidemic drugs operating through activation of PPARalpha, whereas glitazones are insulin sensitizers activating PPARgamma. In addition, these drugs exert pleiotropic and anti-inflammatory actions. This review will focus on the different effects of fibrates and glitazones, as measured by biomarker modulation, on the development of atherosclerosis and cardiovascular disease.

Animals↗
PubMed2005

The anti-obesity effect of rimonabant is associated with an improved serum lipid profile.

We investigated the effects of chronic treatment with the CB1 receptor antagonist rimonabant (10 mg/kg/day p.o. for 10 weeks) in mice with established obesity (5-month high-fat diet). Untreated obese mice showed a weight gain of 46% (45.0 +/- 0.6 g vs. 30.8 +/- 0.5 g) compared with age-matched animals fed a standard diet. Rimonabant treatment, commencing after 5-month high-fat diet, produced a marked and sustained decrease in body weight (34.5 +/- 0.8 g vs. 47.2 +/- 0.5 g in the high-fat vehicle group, p < 0.001). The anti-obesity effect of rimonabant was similar to that obtained by switching obese mice from high-fat diet to standard laboratory diet during 10 weeks (final weight 33.7 +/- 0.6 g) and was associated with only transient (14 days) reduction in energy intake. Serum leptin, insulin and glucose levels were markedly elevated in obese animals. Rimonabant treatment significantly reduced these elevations (leptin -81%, insulin -78%, glucose -67%, p < 0.001 in all cases vs. high-fat vehicle group). In addition, rimonabant treatment modestly but significantly increased serum adiponectin levels (+18%, p < 0.05 vs. high-fat vehicle group). Obese mice demonstrated abnormal serum lipid profiles. Although rimonabant did not modify high-density lipoprotein cholesterol (HDLc) and had modest effects on total cholesterol, it significantly reduced triglycerides and low-density lipoprotein cholesterol (LDLc) and, notably, increased the HDLc/LDLc ratio (12.4 +/- 0.8 vs. 7.9 +/- 0.2 in high-fat vehicle group, p < 0.001). Therefore, in a model of established obesity, chronic rimonabant treatment produces a marked and sustained decrease in body weight (equivalent to that achieved by dietary change) which is associated with favourable modifications in serum biochemical and lipid profiles.

Adiponectin↗
PubMed2005

PPARgamma and atherosclerosis.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)gamma regulates a number of cellular processes that affect glucose homeostasis, endothelial function and vessel wall inflammation, as well as protecting against cardiovascular complications that occur in diabetes. Thiazolidinediones are PPARgamma agonists that are in clinical use for the treatment of type 2 diabetes. Accumulating evidence indicates that thiazolidinediones may exert cardioprotective effects at each stage of atherogenesis. SCOPE: This paper reviews preclinical and clinical evidence (identified from a search of MEDLINE databases) supporting a beneficial cardiovascular effect of thiazolidinediones and discusses the implications of these data for the optimal use of thiazolidinediones in clinical practice. FINDINGS: In vitro animal model and clinical studies indicate that thiazolidinediones correct endothelial dys function, suppress chronic inflammatory processes, reduce fatty streak formation, delay plaque evolution and vessel wall thickening and enhance plaque stabilization and regression. CONCLUSION: Thus, thiazolidinediones show potential as potent anti-inflammatory, antithrombotic agents that could both improve glucose levels and the long-term cardio vascular risk related to atherosclerosis in patients with type 2 diabetes.

Animals↗
PubMed2005

[Glitazones and atherosclerosis].

Atherosclerosis is a vascular disease, appearing early in life, and developing gradually and progressively, from the initial local inflammatory lesions, a stage at which endothelial dysfunction is already present, to the ultimate stage, culminating in atherosclerotic plaque rupture followed by thrombogenesis. Glitazones, specific agonists for the nuclear receptor PPARgamma, act at each stage of the atherogenesis process, and therefore are likely to convey cardioprotective activities in type 2 diabetic patients as well as in non-diabetic patients at high cardiovascular risk (glucose intolerant subjects with or without associated metabolic syndrome). In this review, we summarize the main stages of atherosclerosis progression and their pathophysiological mechanisms, and the results of studies carried out with glitazones, either in in vitro experimental models or in vivo in various animal models, as well as results of recent studies in type 2 diabetic patients, which support the concept for a cardioprotective action of glitazones.

Animals↗
PubMed2004

Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors expressed in macrophages where they control cholesterol homeostasis and inflammation. In an attempt to identify new PPARalpha and PPARgamma target genes in macrophages, a DNA array-based global gene expression profiling experiment was performed on human primary macrophages treated with specific PPARalpha and PPARgamma agonists. Surprisingly, AdipoR2, one of the two recently identified receptors for adiponectin, an adipocyte-specific secreted hormone with anti-diabetic and anti-atherogenic activities, was found to be induced by both PPARalpha and PPARgamma. AdipoR2 induction by PPARalpha and PPARgamma in primary and THP-1 macrophages was confirmed by Q-PCR analysis. Interestingly, treatment with a synthetic LXR agonist induced the expression of both AdipoR1 and AdipoR2. Furthermore, co-incubation with a PPARalpha ligand and adiponectin resulted in an additive effect on the reduction of macrophage cholesteryl ester content. Finally, AdipoR1 and AdipoR2 are both present in human atherosclerotic lesions. Moreover, AdipoR1 is more abundant than AdipoR2 in monocytes and its expression decreases upon differentiation into macrophages, whereas AdipoR2 remains constant. In conclusion, AdipoR1 and AdipoR2 are expressed in human atherosclerotic lesions and macrophages and can be modulated by PPAR and LXR ligands, thus identifying a mechanism of crosstalk between adiponectin and these nuclear receptor signaling pathways.

Carotid Artery Diseases↗
PubMed2004

Inflammation, dyslipidaemia, diabetes and PPars: pharmacological interest of dual PPARalpha and PPARgamma agonists.

Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARalpha agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARgamma agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARalpha and PPARgamma agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARalpha and PPARalpha agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes.

Cardiovascular Diseases↗
PubMed2004

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells.

Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C(19) steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3beta-hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C(19) steroid and estrogen production.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

PPAR alpha, fibrates, lipid metabolism and inflammation.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors belonging to the nuclear receptor superfamily. Three PPAR isotypes have been characterised: alpha, beta/delta and gamma. Identification of selective ligands and gene targeting studies have allowed determination of subtype-specific functions and the therapeutic potential of these receptors. Thus, PPAR alpha plays a prominent role in several physiological processes including the control of lipid and lipoprotein metabolism, glucose homoeostasis and the inflammatory response. Here, we update the potential of PPAR alpha activation in the treatment of metabolic disorders and related cardiovascular complications.

Arteriosclerosis↗