Role Of Peroxisome Proliferator-activated Receptors Research Articles

Fenofibrate, a PPARα agonist, has renoprotective effects in mice by enhancing renal lipolysis

As renal lipotoxicity can lead to chronic kidney disease (CKD), we examined the role of peroxisome proliferator-activated receptor (PPAR)-α, a positive regulator of renal lipolysis. Feeding mice a high-fat diet induced glomerular injury, and treating them with fenofibrate, a PPARα agonist, increased the expression of lipolytic enzymes and reduced lipid accumulation and oxidative stress in glomeruli, while inhibiting the development of albuminuria and glomerular fibrosis. In mice given an overload of free fatty acid-bound albumin to induce tubulointerstitial injury, fenofibrate attenuated the development of oxidative stress, macrophage infiltration, and fibrosis, and enhanced lipolysis in the renal interstitium. Fenofibrate inhibited palmitate-induced expression of profibrotic plasminogen activator inhibitor-1 (PAI-1) in cultured mesangial cells, and the expression of both monocyte chemoattractant protein-1 and PAI-1 in proximal tubular cells along with the overexpression of lipolytic enzymes. Thus, fenofibrate can attenuate lipotoxicity-induced glomerular and tubulointerstitial injuries, with enhancement of renal lipolysis. Whether amelioration of renal lipotoxicity by PPARα agonists will turn out to be a useful strategy against CKD will require direct testing.

Modulation of inflammatory response and parasitism by 15-Deoxy-Δ12,14 prostaglandin J2 in Trypanosoma cruzi-infected cardiomyocytes

Trypanosoma cruzi infection produces an intense inflammatory response in diverse tissues including the heart. The inflammatory reaction is critical for the control of the parasites’ proliferation and evolution of Chagas disease. 15-Deoxy-Δ12,14 prostaglandin J2 (15dPGJ2) can repress the inflammatory response in many experimental models. However, the precise role of peroxisome proliferator-activated receptor γ (PPARγ) ligands in T. cruzi infection or in Chagas disease is poorly understood. This work reports the first evidence that 15dPGJ2 treatment increases the number of intracellular parasites as shown by fluorescence microscopy and it is also able to inhibit the expression and activity of different inflammatory enzymes such as inducible nitric oxide synthase (NOS-2), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), as well as pro-inflammatory cytokine (TNF-α and IL-6) mRNA expression in neonatal mouse cardiomyocytes after T. cruzi infection. Transfection of cardiomyocytes with small interfering RNA (siRNA) induces silencing of PPARγ and impairs the effects of 15dPGJ2 on the modulation of pro-inflammatory enzymes. Moreover, transfection restores the ability of these cells to control the intracellular growth of T. cruzi. We also found that PPARγ-independent pathways are involved, since 15dPGJ2 also exerts its effect through extracellular signal-regulated kinases-mitogen-activated protein kinase (Erk-MAPK) and nuclear factor-κB (NF-κB). The use of specific pharmacological inhibitors confirmed these findings. Our data point out that 15dPGJ2 is a potent modulator of the inflammatory process and regulator of parasites growth through PPARγ-dependent and independent (Erk-MAPK- and NF-κB) pathways in T. cruzi infected neonatal cardiac cells.

Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ

Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation.

Role of Peroxisome Proliferator-Activated Receptor α in Diabetic Nephropathy

With a developing worldwide epidemic of diabetes mellitus, the renal complications associated with diabetes have become a serious health concern. Primary therapy for treating diabetic nephropathy is a multifactorial process. Peroxisome proliferator-activated receptor alpha (PPARα) agonists have been used primarily in clinical practice for the treatment of dyslipidemia and insulin resistance. Given that PPARα expression and regulation of metabolic pathways are involved in oxidative stress, inflammation, blood pressure regulation, and the renin-angiotensin aldosterone system, PPARα likely influences the development and pathogenesis of diabetic nephropathy via indirect effects on glucose and lipid homeostasis and also by direct action on the kidneys. These findings suggest that PPARα may become an important therapeutic target for treating diabetic renal complications.

Role of Peroxisome Proliferator-activated Receptor δ/β in Hepatic Metabolic Regulation

Pharmacological activation of peroxisome proliferator-activated receptor δ/β (PPARδ/β) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus-mediated liver-restricted PPARδ activation reduces fasting glucose levels in chow- and high fat-fed mice. This effect is accompanied by hepatic glycogen and lipid deposition as well as up-regulation of glucose utilization and de novo lipogenesis pathways. Promoter analyses indicate that PPARδ regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PPARγ co-activator-1β. Assessment of the lipid composition reveals that PPARδ increases the production of monounsaturated fatty acids, which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPARδ-infected livers exhibit less damage and show a reduction in JNK stress signaling, suggesting that PPARδ-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPARδ also results in a secondary effect on AMP-activated protein kinase activation, which likely contributes to the glucose-lowering activity. Collectively, our data suggest that PPARδ controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPARδ agonists to manage hyperglycemia and insulin resistance.

The role of peroxisome proliferator-activated receptor γ, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage

Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in neurons and glia, and its synthetic agonist, rosiglitazone (RSG), regulates inflammatory process and has neuroprotective effects against neurological disorders. In the present study, we examined the role of PPARγ in the hippocampal CA1 region (CA1) after transient cerebral ischemia and the neuroprotective effects of RSG on ischemic damage. RSG attenuated neuronal damage in the ischemic CA1, not showing perfect neuroprotection: the RSG appeared to delay neuronal death after ischemia/reperfusion (I/R). PPARγ immunoreactivity and protein levels were increased after I/R, and most of PPARγ-immunoreactive cells colocalized with microglia, not astrocytes. In addition, RSG attenuated glial activation and increased IL-4 and IL-13 levels in the ischemic CA1. These results indicate that PPARγ increases and expresses in microglia after I/R, and that RSG delays neuronal damage by interfering with glial activations and increases anti-inflammatory cytokines in response to ischemic damage.

Advanced glycation end products downregulates peroxisome proliferator-activated receptor γ expression in cultured rabbit chondrocyte through MAPK pathway

Accumulation of advanced glycation end products (AGEs) which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of osteoarthritis. The objective of the present study was to investigate the role of peroxisome proliferator-activated receptor γ (PPARγ) in AGEs-mediated chondrocytes damage. In the cultured rabbit chondrocytes, our results show that the PPARγ agonist pioglitazone can concentration-dependently inhibit the AGEs-induced expression of TNF-α and MMP-13. Several studies have shown that activation of PPARγ may interfere with several signaling pathways regulating the proinflammatory genes in vivo and vitro experiments, but little is known regarding their expression and regulation in cartilage. Thus the effect of AGEs on PPARγ expression was next examined. Reverse transcription (RT)-PCR analysis revealed that AGEs treatment of chondrocytes downregulated PPARγ expression in a time- and concentration-dependent manner. AGEs-induced a significant downregulation in PPARγ mRNA at 48 h and the maximum effect was found at 100 μg/ml AGEs. This effect was significantly depressed by the anti-RAGE antibody. Specific inhibitors of the mitogen-activated protein kinases (MAPK) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented AGEs-induced downregulation of PPARγ expression. In conclusion, AGEs may be responsible for PPARγ downregulation via a mechanism involving activation of the MAPK (p38 and JNK), and this downregulation might play a key role in AGEs-induced production of TNF-α and MMP-13.

Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

Reverse crosstalk of TGFβ and PPARβ/δ signaling identified by transcriptional profiling

Previous work has provided strong evidence for a role of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and transforming growth factor-β (TGFβ) in inflammation and tumor stroma function, raising the possibility that both signaling pathways are interconnected. We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation, which revealed a substantial, mostly reverse crosstalk of both pathways and identified distinct classes of genes. A major class encompasses classical PPAR target genes, including ANGPTL4, CPT1A, ADRP and PDK4. These genes are repressed by TGFβ, which is counteracted by PPARβ/δ activation. This is mediated, at least in part, by the TGFβ-induced recruitment of the corepressor SMRT to PPAR response elements, and its release by PPARβ/δ ligands, indicating that TGFβ and PPARβ/δ signals are integrated by chromatin-associated complexes. A second class represents TGFβ-induced genes that are downregulated by PPARβ/δ agonists, exemplified by CD274 and IL6, which is consistent with the anti-inflammatory properties of PPARβ/δ ligands. Finally, cooperative regulation by both ligands was observed for a minor group of genes, including several regulators of cell proliferation. These observations indicate that PPARβ/δ is able to influence the expression of distinct sets of both TGFβ-repressed and TGFβ-activated genes in both directions.

Effects of Intensive Blood Pressure Control in the Management of Patients With Type 2 Diabetes Mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

To appreciate the importance of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,1 one needs to remember that the systolic blood pressure (BP) target currently recommended by major guidelines for diabetic patients, that is, 130 mm Hg, except in the Appropriate Blood Pressure Control in Diabetes Study (ABCD) normotensive trial,7 which consisted of only a few hundred patients and had changes in creatinine clearance as the primary end point. Thus, ACCORD represents the only large-scale randomized trial that provides information on what happens to the cardiovascular risk of diabetic patients when SBP is reduced to 130 mm Hg as a result of randomization to the usual (rather than the tight) BP control treatment strategy. Thus, the message from ACCORD to guidelines and clinical practice is that in diabetic patients it is not necessary to adopt …

PPARα contributes to colonic protection in mice with DSS-induced colitis

Inflammatory bowel disease (IBD) is characterized by repeated chronic inflammation of the gastrointestinal tract. We have used the complementary model of colonic inflammation to examine the roles of peroxisome proliferator-activated receptor α (PPARα) in colonic inflammation and thus its possible role in IBD. We characterized an innate immune-mediated model of colitis induced by dextran sulfate sodium (DSS). Mice with DSS-induced colitis were injected with Wy-14643 (2 mg/kg) as a PPARα agonist every day from day 0 to day 5. We show that mice given Wy-14643 were less susceptible to experimental acute colitis induced by DSS, and this decreased susceptibility was correlated with decreased production of IFNγ, IL-1β, IL-6, and TNF-α. Our findings suggest that PPARα has a role in controlling colonic inflammation and mucosal tissue homeostasis.

Upregulation of PPARβ/δ Is Associated with Structural and Functional Changes in the Type I Diabetes Rat Diaphragm

BackgroundDiabetes mellitus is associated with alterations in peripheral striated muscles and cardiomyopathy. We examined diaphragmatic function and fiber composition and identified the role of peroxisome proliferator-activated receptors (PPAR α and β/δ) as a factor involved in diaphragm muscle plasticity in response to type I diabetes.Methodology/Principal FindingsStreptozotocin-treated rats were studied after 8 weeks and compared with their controls. Diaphragmatic strips were stimulated in vitro and mechanical and energetic variables were measured, cross bridge kinetics assessed, and the effects of fatigue and hypoxia evaluated. Morphometry, myosin heavy chain isoforms, PPAR α and β/δ gene and protein expression were also assessed. Diabetes induced a decrease in maximum velocity of shortening (−14%, P<0.05) associated with a decrease in myosin ATPase activity (−49%, P<0.05), and an increase in force (+20%, P<0.05) associated with an increase in the number of cross bridges (+14%, P<0.05). These modifications were in agreement with a shift towards slow myosin heavy chain fibers and were associated with an upregulation of PPARβ/δ (+314% increase in gene and +190% increase in protein expression, P<0.05). In addition, greater resistances to fatigue and hypoxia were observed in diabetic rats.Conclusions/SignificanceType I diabetes induced complex mechanical and energetic changes in the rat diaphragm and was associated with an up-regulation of PPARβ/δ that could improve resistance to fatigue and hypoxia and favour the shift towards slow myosin heavy chain isoforms.

Long Chain Acyl-CoA Synthetase-3 Is a Molecular Target for Peroxisome Proliferator-activated Receptor δ in HepG2 Hepatoma Cells

ACSL3 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues in an isozyme-specific manner. Our previous studies showed that ACSL3 was transcriptionally up-regulated by the cytokine oncostatin M (OSM) in HepG2 cells, accompanied by reduced cellular triglyceride content and enhanced beta-oxidation. In this study, we investigated the molecular mechanism underlying the OSM-induced activation of ACSL3 gene transcription in HepG2 cells. We showed that OSM treatment resulted in a coordinated elevation of mRNA levels of ACSL3 and peroxisome proliferator-activated receptor delta (PPARdelta). The effect of OSM on ACSL3 mRNA expression was inhibited by cellular depletion of PPARdelta. By utilizing a PPARdelta agonist, L165041, we demonstrated that activation of PPARdelta led to increases in ACSL3 promoter activity, mRNA level, and protein level in HepG2 cells. Analysis of the ACSL3 promoter sequence identified two imperfect PPAR-responsive elements (PPRE) located in the ACSL3 promoter region -944 to -915, relative to the transcription start site. The up-regulation of ACSL3 promoter activity by PPARdelta was abolished by deletion of this PPRE-containing region or mutation to disrupt the binding sites. Direct interactions of PPARdelta with ACSL3-PPRE sequences were demonstrated by gel mobility shift and chromatin immunoprecipitation assays. Finally, we provided in vivo evidence showing that activation of PPARdelta by L165041 in hamsters increased ACSL3 mRNA and protein levels in the liver. These new findings define ACSL3 as a novel molecular target of PPARdelta in HepG2 cells and provide a regulatory mechanism for ACSL3 transcription in liver tissue.

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-gamma in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-gamma expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, alpha-smooth muscle actin (alpha-SMA) and smooth muscle 22alpha (SM22alpha), and enhanced proliferation and migration. PPAR-gamma overexpression rescued the expression of alpha-SMA and SM22alpha, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-gamma silencing exerted the opposite effect. Activating PPAR-gamma using rosiglitazone in vivo up-regulated aortic alpha-SMA and SM22alpha expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-gamma inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-gamma silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-gamma overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-gamma inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-gamma expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.

PPARs in Bone: The Role in Bone Cell Differentiation and Regulation of Energy Metabolism

Obesity, diabetes, and osteoporosis are major public health concerns. Current estimates indicate that the US population consists of 25% obese, 30% diabetic and prediabetic, and, among the elderly, 50% of all osteoporotic individuals. Mechanistically, these pathologies share several features including common regulators of bone homeostasis and energy metabolism. Peroxisome proliferator-activated receptors (PPARs) represent a family of proteins that control energy turnover in adipose, liver, and muscle tissue. These proteins also control bone turnover and regulate bone cell differentiation. Recent evidence suggests that bone is an organ integral to energy metabolism not only with respect to energy storage, but also as an organ regulating systemic energy homeostasis. In this article, we review current knowledge on the role of PPARs in bone metabolism and bone cell differentiation. We also discuss the role of bone fat in modulation of bone marrow microenvironment and its possible contribution to the systemic regulation of energy metabolism.

GW0742, A HIGH-AFFINITY PPAR -β/δ AGONIST, INHIBITS ACUTE LUNG INJURY IN MICE

Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR) beta/delta in the pathogenesis of a number of diseases. The aim of this study was to investigate the effects of a high-affinity PPAR-beta/delta agonist, GW0742, in a mouse model of carrageenan (CAR)-induced pleurisy. Injection of CAR into the pleural cavity of mice elicited an acute inflammatory response characterized by accumulation of fluid containing a large number of neutrophils (polymorphonuclear leukocytes) in the pleural cavity, infiltration of polymorphonuclear leukocytes in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate, TNF-alpha, and IL-1beta. Furthermore, CAR induced lung apoptosis (Bax and Bcl-2 expression), and nitrotyrosine formation was determined by immunohistochemical analysis of lung tissues. Administration of GW0742 (0.3 mg/kg, i.p. bolus) 30 min before and 30 min after a challenge with CAR caused a reduction in all the parameters of inflammation measured. Thus, based on these findings, we propose that a PPAR-beta/delta agonist such as GW0742 may be useful in the treatment of various inflammatory diseases.

Evidence for the Role of Peroxisome Proliferator-Activated Receptor-β/δ in the Development of Spinal Cord Injury

Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR)-beta/delta in the pathogenesis many diseases. The aim of the present study was to evaluate the contribution of PPAR-beta/delta in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742), a high-affinity PPAR-beta/delta agonist. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of inflammatory mediators, tissue damage, and apoptosis. GW0742 treatment (0.3 mg kg(-1) i.p.) 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-kappaB activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, FasL, Bax, and Bcl-2 expression). Moreover, GW0742 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of GW0742 are related to activation of the PPAR-beta/delta receptor, we also investigated the effect of PPAR-beta/delta antagonist methyl 3-({[2-(methoxy)-4 phenyl]amino}sulfonyl)-2-thiophenecarboxylate (GSK0660) on the protective effects of GW0742. GSK0660 (1 mg/kg i.p. 30 min before treatment with GW0742) significantly blocked the effect of the PPAR-beta/delta agonist and thus abolished the protective effect. Our results clearly demonstrate that GW0742 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

027 Protective role of peroxisome proliferator-activated receptor Î/Î′ in cardiac dysfunction and organ injury/inflammation caused by endotoxin in mice

Peroxisome proliferator-activated receptor (PPAR)-I2/I′ is a transcription factor that belongs to the PPAR nuclear hormone receptor family. There is little information about the ligands of PPAR-I2/I′ and the effect of...

PPARs in the Renal Regulation of Systemic Blood Pressure.

Recent research has revealed roles for the peroxisome proliferator activated receptor (PPAR) family of transcription factors in blood pressure regulation, expanding the possible therapeutic use of PPAR ligands. PPARα and PPARγ modulate the renin-angiotensin-aldosterone system (RAAS), a major regulator of systemic blood pressure and interstitial fluid volume by transcriptional control of renin, angiotensinogen, angiotensin converting enzyme (ACE) and angiotensin II receptor 1 (AT-R1). Blockade of RAAS is an important therapeutic target in hypertension management and attenuates microvascular damage, glomerular inflammation and left ventricular hypertrophy in hypertensive patients and also show antidiabetic effects. The mechanisms underlying the benefits of RAAS inhibition appear to involve PPARγ-regulated pathways. This review summarizes current knowledge on the role of PPARs in the transcriptional control of the RAAS and the possible use of PPAR ligands in the treatment of RAAS dependent hypertension.

Peroxisome Proliferator-Activated Receptor-α Control of Lipid and Glucose Metabolism in Human White Adipocytes

This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPAR alpha and PPAR gamma actions in these cells. Primary cultures of human fat cells were treated with the PPAR alpha agonist GW7647 or the PPAR gamma agonist rosiglitazone. Changes in gene expression were determined using DNA microarrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of beta-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPAR alpha agonist. GW7647-induced alterations were abolished by a treatment with a PPAR alpha antagonist. Small interfering RNA-mediated extinction of PPAR alpha gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and beta-oxidation. Altogether these results show that PPAR alpha can selectively up-regulate beta-oxidation and decrease glucose utilization in human white adipocytes.