Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.
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 PPAR␣ and PPAR␥ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPAR␣ is already present in undifferentiated monocytes, PPAR␥ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPAR␣ resides constitutively in the cytoplasm, whereas PPAR␥ is predominantly nuclear localized. Transient transfection experiments indicate that PPAR␣ and PPAR␥ are transcriptionally active after ligand stimulation. Ligand activation of PPAR␥, but not of PPAR␣, 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 PPAR␣ and PPAR␥ ligands induce apoptosis of macrophages activated with tumor necrosis factor ␣/interferon ␥. Finally, PPAR␥ inhibits the transcriptional activity of the NFB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.
Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERR␣ have not been well defined. To identify ERR␣-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERR␣. ERR␣ upregulated a subset of PGC-1␣ target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C 2 C 12 myotubes, and cardiac and skeletal muscle of ERR␣ ؊/؊ mice. Consistent with the gene expression results, ERR␣ increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERR␣ are known targets for the nuclear receptor PPAR␣, and therefore, the interaction between these regulatory pathways was explored. ERR␣ activated PPAR␣ gene expression via direct binding of ERR␣ to the PPAR␣ gene promoter. Furthermore, in fibroblasts null for PPAR␣ and ERR␣, the ability of ERR␣ to activate several PPAR␣ targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1␣ was also shown to activate ERR␣ gene expression. We conclude that ERR␣ serves as a critical nodal point in the regulatory circuitry downstream of PGC-1␣ to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.The essential role of nuclear receptors in regulating various cellular metabolic pathways is becoming increasingly evident. In recent years, various nuclear receptors that do not respond to classical endocrine ligands, including peroxisome proliferator-activated receptors (PPARs), liver X receptors, farnesoid X receptors, and retinoid X receptors, have been shown to be activated by low-affinity diet-derived ligands (6,11,26,44). Activation of these receptors by metabolite ligands such as fatty acids, oxysterols, and bile acids elicits downstream transcriptional regulation of pathways involved in synthesis and catabolism of these ligands. The remaining receptors, designated orphan receptors because endogenous ligands have not been identified, comprise the largest subcategory of nuclear receptors. It is likely that orphan receptors serve additional roles in regulating intermediary metabolism. Linking orphan receptors to target genes is an important goal in the field of nuclear receptor biology. Target gene profiling will also provide insights for determining what metabolites serve as endogenous ligands for these receptors and, in turn, for developing pharmacologic interventions designed to regulate cellular metabolism.One group of orphan receptors recently identified as candidate regulators of cellular metabolism are the estrogen-related recepto...
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...
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPARalpha and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPARalpha expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans.
Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid-activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells.
We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68 + ) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRα are increased in plaque CD68 + cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe -/-mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68 + cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe -/-mice, or from Apoe -/-mice with BM deficiency of LXRα or LXRβ, into WT recipients. Plaques from both LXRα-and LXRβ-deficient Apoe -/-mice exhibited impaired regression. In addition, the CD68 + cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRα and LXRβ levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68 + cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice.
Risk of coronary artery disease (CAD) is determined by a combination of genetic and environmental factors which influence plasma lipid homeostasis, haemostasis and inflammation. Peroxisome proliferator activated receptor alpha (PPARa) is a ligand-inducible transcription factor [1] which regulates the expression of genes involved in fatty acid oxidation, extracellular lipid metabolism, haemostasis [2] and inflammation [3]. Ligands for PPARa include long chain fatty acids, eicosanoids, peroxisome proliferators, non-steroidal anti-inflammatory drugs and the fibrate class of hypolipidaemic drugs [4±6]. PPARa is highly expressed in tissues with a high rate of fatty Diabetologia (2000) Methods. The human PPARa gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays.Results. We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. Conclusion/interpretation. Naturally occurring variation alters PPARa function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARa is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes. [Diabetologia (2000) 43: 673±680]
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