Abstract-Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPAR␣ mediates the hypolipidemic action of fibrates, PPAR␥ is the receptor for the antidiabetic glitazones. PPAR␣ is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the -oxidative degradation of fatty acids. PPAR␥ is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPAR/␦ is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPAR␣ controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPAR␣ and PPAR␥ regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall. Key Words: nuclear receptors Ⅲ HDL Ⅲ inflammation Ⅲ cholesterol Ⅲ atherosclerosis T he metabolic syndrome, which can be defined as the clustering of cardiovascular risk factors with insulin resistance, is characterized by the simultaneous presence of one or more of the following metabolic disorders: glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances, and hypertension. Peroxisome proliferator-activated receptors (PPARs) modulate these metabolic risk factors for cardiovascular disease associated with the metabolic syndrome. Whereas previous articles have summarized our present understanding of the role of PPARs in the control of glucose homeostasis, insulin resistance, and hypertension (see reviews 1,2 ), the present review will focus on the plasma lipid-controlling actions of PPARs and their effects on atherogenesis. Levels of Control of PPAR ActivityFatty acids (FAs) and FA-derived compounds are natural ligands for PPAR␣ and PPAR␥. Natural eicosanoids derived from arachidonic acid via the lipoxygenase pathway, such as 8-S-hydroxytetraenoic acid and leukotriene B4, and oxidized phospholipids from oxidized lipoproteins activate PPAR␣. 3 PPAR␥ is a receptor for eicosanoid metabolites formed via the cyclooxygenase pathway, eg, prostaglandins, such as PGJ 2 , PGH 1 , and PGH 2 , 4 and via the lipoxygenase pathway (15-hydroxytetraenoic acid). 3 Simila...
Rev-Erb␣ (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor ␣ gene. Rev-Erb␣ mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor ␥ (PPAR␥) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erb␣ expression is induced by PPAR␥ activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Adipocyte differentiation is a complex biological process, which is reflected at the molecular level by the transcriptional activation of a number of adipocyte-specific genes and by the acquisition of the ability to accumulate cytoplasmic lipid droplets (1-3). The nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥, 1 NR1C3) (4, 5) and members of the CCAAT enhancer-binding protein (C/EBP) family (6 -12) play key roles in this adipogenic process. In addition, the adipocyte differentiation and determination factor-1 (SREBP-1/ADD1) appears to promote adipocyte differentiation by activating the expression of PPAR␥ and increasing the synthesis of endogenous PPAR␥ ligands (13-15). Members of the PPAR family bind as heterodimers with the retinoid X receptors (RXR) to specific response elements termed peroxisome proliferator response elements (PPRE) (for review see Ref. 16). These PPREs usually consist of a direct repeat of the PuGGTCA motif spaced by one nucleotide (DR1). The transcriptional activity of the PPARs is activated by a number of different fatty acid metabolites, most notably products of the cycloxygenase and lipoxygenase pathways. In addition, a large number of synthetic compounds are known to be potent and subtype specific PPAR ligands. For example, thiazolidinedione compounds used as insulin sensitizers in the treatment of type II diabetes are high affinity PPAR␥ ligands (17).Rev-Erb␣ (NR1D1) is another nuclear receptor, the expression of which is induced during adipocyte differentiation (18). Rev-Erb␣ is highly expressed in adipose tissue but also in skeletal muscle, liver and brain (18 -21). Since no ligand has been identified so far, Rev-Erb␣ is considered as an orphan member of the nuclear receptor superfamily. Rev-Erb␣ has been shown to act as a negative regulator of transcription (22) binding either as monomer on nuclear receptor half-site motifs flanked 5Ј by an A/T rich sequence (A/T PuGGTCA), or as a homodimer to a direct repeat of the PuGGTCA motif spaced by two nucleotides (DR2).We have previously shown that PPAR␣ activates the expression of Rev-Erb␣ through an atypical PPRE, a DR-2 element, in the Rev-Erb␣ promoter (23). Transcriptional activation by PPAR␥ through a DR-2 element has so far not been reported. However, since Rev-Erb␣ is induced during the course of adipocyte differentiation, we decided to investigate whether PPAR␥ could be involved in transcriptional induction of RevErb␣ expression in adipocytes. Furth...
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