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PPAR
Kinds of PPAR Terms modified by PPAR Selected AbstractsEffects of cevoglitazar, a dual PPAR,/, agonist, on ectopic fat deposition in fatty Zucker ratsDIABETES OBESITY & METABOLISM, Issue 6 2009D. Laurent Aim:, By acting as both insulin sensitizers and lipid-lowering agents, dual-acting peroxisome proliferator-activated receptors ,/, (PPAR,/,) agonists may be used to improve glucose tolerance in type 2 diabetic patients without inducing adiposity and body weight gain. Here, in an animal model of obesity and insulin resistance, the metabolic response to cevoglitazar, a dual PPAR,/,, was characterized using a combination of in vivo and ex vivo magnetic resonance methodologies and compared to treatment effects of fenofibrate, a PPAR, agonist, and pioglitazone, a PPAR, agonist. Methods:, Four groups of fatty Zucker rats: (i) Vehicle; (ii) fenofibrate 150 mg/kg; (iii) pioglitazone 30 mg/kg; and (iv) cevoglitazar 5 mg/kg were investigated before and after treatment. Animals were fed a fat-enriched (54% kcal fat) diet for 6 weeks, 2 weeks high of fat,exposure alone followed by a 4-week dosing period. Results and conclusions:, Cevoglitazar was as effective as pioglitazone at improving glucose tolerance. However, unlike pioglitazone, both fenofibrate and cevoglitazar reduced BW gain and adiposity, independent of food intake. All three treatment regimens normalized intramyocellular lipids. Metabolic profiling showed that in the muscle cevoglitazar improves the lipid profile via both PPAR,- and PPAR,-mediated mechanisms. Pioglitazone reduced hepatic lipid accumulation, while cevoglitazar and fenofibrate reduced hepatic lipid concentration below baseline levels (p < 0.05). Metabolic profiling showed that in the liver, cevoglitazar functions largely through PPAR, agonism resulting in increased ,-oxidation. Cevoglitazar only induced small changes to the lipid composition of visceral fat. In subcutaneous fat, however, cevoglitazar induced changes similar to those observed with fenofibrate suggesting export of fatty acids from this depot. [source] Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-,/-, activator propertiesDIABETES OBESITY & METABOLISM, Issue 1 2008Yuhao Li PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-, is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-, participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-, or PPAR-, agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-, and PPAR-, activators, as well as their potential to modulate vascular disease, combined PPAR-,/-, activation has recently emerged as a promising concept, leading to the development of mixed PPAR-,/-, activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-, and PPAR-, activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-,/-, activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications. [source] Discordance between intramuscular triglyceride and insulin sensitivity in skeletal muscle of Zucker diabetic rats after treatment with fenofibrate and rosiglitazoneDIABETES OBESITY & METABOLISM, Issue 5 2007K. J. Nadeau Aim:, Intramyocellular triglyceride (IMTG) correlates with insulin resistance, but there is no clear causal relationship. Insulin resistance and associated hyperinsulinaemia may increase IMTG, via the insulin-regulated transcription factor, sterol regulatory element,binding protein 1 (SREBP-1). PPAR agonists may also affect IMTG via changes in insulin sensitivity, SREBP-1 or other factors. Methods:, We examined skeletal muscle IMTG and SREBP-1 expression, and metabolic parameters in Zucker diabetic fatty rats (ZDF) after 25 weeks of PPAR-, or PPAR-, administration. Results:, Compared with Zucker lean rats (ZL), untreated ZDF had significantly higher weights, serum glucose, insulin, free fatty acids, total cholesterol and triglycerides. IMTG and SREBP-1c messenger RNA (mRNA) were also higher in untreated ZDF; both were decreased by fenofibrate (FF). Rosiglitazone (Rosi), despite marked improvement in glycaemia, hyperinsulinaemia and hyperlipidaemia, failed to affect SREBP-1 expression, and increased body weight and IMTG. Rosi/FF combination caused less weight gain and no IMTG increase, despite metabolic effects similar to Rosi alone. Conclusions:, IMTG and SREBP-1c mRNA are high in the ZDF. FF and Rosi both improved insulin sensitivity but had opposite effects on IMTG. Thus, there was a clear discordance between insulin sensitivity and IMTG with PPAR agonists, indicating that IMTG and insulin sensitivity do not share a simple relationship. [source] Insulin resistance , a common link between type 2 diabetes and cardiovascular diseaseDIABETES OBESITY & METABOLISM, Issue 3 2006Harold E. Lebovitz Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the ,common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPAR, agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPAR, (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPAR, and PPAR, activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD. [source] PPAR, and the thiazolidinediones: molecular basis for a treatment of ,Syndrome X'?DIABETES OBESITY & METABOLISM, Issue 4 2002C. Sewter First page of article [source] Advanced glycation end products-induced apoptosis attenuated by PPAR, activation and epigallocatechin gallate through NF-,B pathway in human embryonic kidney cells and human mesangial cellsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2010Yao-Jen Liang Abstract Background Diabetic nephropathy has attracted many researchers' attention. Because of the emerging evidence about the effects of advanced glycation end products (AGEs) and receptor of AGE (RAGE) on the progression of diabetic nephropathy, a number of different therapies to inhibit AGE or RAGE are under investigation. The purpose of the present study was to examine whether peroxisome proliferator-activated receptor , (PPAR,) agonist (L-165041) or epigallocatechin gallate (EGCG) alters AGE-induced pro-inflammatory gene expression and apoptosis in human embryonic kidney cells (HEK293) and human mesangial cells (HMCs). Methods The HEK cells and HMC were separated into the following groups: 100 µg/mL AGE alone for 18 h; AGE treated with 1 µM L-165041 or 10 µM EGCG, and untreated cells. Inflammatory cytokines, nuclear factor-,B pathway, RAGE expression, superoxide dismutase and cell apoptosis were determined. Results AGE significantly increased tumour necrosis factor-, (TNF-,), a major pro-inflammatory cytokine. The mRNA and protein expression of RAGE were up-regulated. These effects were significantly attenuated by pre-treatment with L-165041 or EGCG. AGE-induced nuclear factor-,B pathway activation and both cells apoptosis were also inhibited by L-165041 or EGCG. Furthermore, both L-165041 and EGCG increased superoxide dismutase levels in AGE-treated HEK cells and HMC. Conclusions This study demonstrated that PPAR, agonist and EGCG decreased the AGE-induced kidney cell inflammation and apoptosis. This study provides important insights into the molecular mechanisms of EGCG and PPAR, agonist in attenuation of kidney cell inflammation and may serve as a therapeutic modality to treat patients with diabetic nephropathy. Copyright © 2010 John Wiley & Sons, Ltd. [source] Diabetes: insulin resistance and derangements in lipid metabolism.DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2005Cure through intervention in fat transport, storage Abstract We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPAR,, or PPAR,, agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening. Copyright © 2004 John Wiley & Sons, Ltd. [source] The mode of action of thiazolidinediones,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Hans Hauner Abstract The thiazolidinediones (TZDs) or ,glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR,), a nuclear receptor. TZD-induced activation of PPAR, alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR, is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-, (TNF-,), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full ,insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of ABCA1 variant on atherogenic dyslipidaemia in patients with Type 2 diabetes treated with rosiglitazoneDIABETIC MEDICINE, Issue 6 2009S. E. Park Abstract Aims, To investigate the effect of two common ATP-binding cassette transporter 1 (ABCA1) polymorphisms (rs4149263 and rs2020927) on atherogenic dyslipidaemia in Korean Type 2 diabetic patients who were treated with rosiglitazone. Patients and methods, Two hundred and fifty-six patients with Type 2 diabetes who had never previously received peroxisome proliferator-activated receptor gamma (PPAR-,) agonists or lipid-lowering treatment were treated with 4 mg of rosiglitazone daily for 12 weeks without any adjustment to their glucose-lowering regimen. The primary outcome was the change in atherogenic index of plasma (AIP), calculated as log [triglyceride (mmol/l)/high-density lipoprotein cholesterol (mmol/l)], before and after rosiglitazone treatment. The effect of rosiglitazone on the change in AIP was compared across the ABCA1 single nucleotide polymorphisms (SNPs) rs41429263 and rs2020927. Results, Before adjustment, the change in AIP at 12 weeks was significantly different across the rs4149263 genotypes [median (interquartile range): ,0.05 (,0.21, 0.09) for TT; 0.02 (,0.09, 0.17) for TC; and 0.11 (0.03, 0.25) for CC; P = 0.003], but not across the rs2020927 [,0.04 (,0.18, 0.10) for TT; 0.03 (,0.17, 0.15) for TC; and ,0.03 (,0.13, 0.10) for CC; P = 0.401]. After controlling for age, gender and duration of diabetes, the presence of the C-allele was significantly associated with an increase in AIP by 0.13 [95% confidence interval (CI), 0.04,0.21; P = 0.003]. This association did not change significantly when body mass index and pretreatment metabolic parameters were additionally controlled for (the change in AIP: 0.14; 95% CI, 0.04,0.24; P = 0.007). Conclusions, The ABCA1 SNP rs4149263 may be associated with the change in atherogenic lipid profile in Type 2 diabetes treated with rosiglitazone. [source] Peroxisome proliferator-activated receptor-, as emerging target in liver diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2010Bernd Schnabl Abstract Liver fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) proteins that occurs in chronic liver disease of any origin, including nonalcoholic steatohepatitis (NASH), alcohol abuse, and viral hepatitis. Cirrhosis occurs with the development of regenerating nodules of hepatocytes and is a major health burden worldwide. Patients with decompensated liver cirrhosis have a poor prognosis, with liver transplantation often being necessary. The current treatment paradigm for patients with hepatic fibrosis is to treat the underlying liver disease. However, if this cannot be achieved, there are currently no effective antifibrotic treatments for patients with chronic liver diseases. With the advent of basic molecular technology providing insight into the mechanisms of the development of hepatic fibrosis, there is now an opportunity to develop therapeutic interventions for human clinical use. In this review, the function of peroxisome proliferator-activated receptor-, (PPAR ,) will be summarized with a special emphasis on ligand activation as potential use in liver disease. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc. [source] Effects of lipid-lowering pharmaceuticals bezafibrate and clofibric acid on lipid metabolism in fathead minnow (Pimephales promelas),ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2009Anna Weston Abstract The lipid-lowering agents bezafibrate and clofibric acid, which occur at concentrations up to 3.1 and 1.6 ,L, respectively, are among the most frequently found human pharmaceuticals in the aquatic environment. In contrast to knowledge about their environmental occurrence, little is known about their effects in the environment. The aim of the present study was to analyze effects of these lipid-lowering agents in fish by focusing on their modes of action, lipid metabolism. Fathead minnows were exposed in aquaria to measured concentrations of 0.1, 1.27, 10.18, 101.56, and 106.7 mg/L bezafibrate and to 1.07, 10.75, and 108.91 mg/L clofibric acid for 14 and 21 d, respectively. After exposure, fish liver was analyzed for expression of peroxisome proliferator-activated receptor , (PPAR,) by quantitative polymerase chain reaction (PCR), and the PPAR-regulated enzyme fatty acyl-coenzyme-A oxidase (FAO) involved in fatty acid oxidation. Bezafibrate had no effect, either on PPAR, expression or on FAO activity, at all concentrations. In contrast, clofibric acid induced FAO activity in male fathead minnows at 108.91 mg/L. No increase in expression of PPAR, messenger ribonucleic acid was observed. Egg production was apparently decreased after 21 d of exposure to 108.91 mg/L clofibric acid. The present study demonstrates that bezafibrate has very little or no effect on PPAR, expression and FAO activity, but clofibric acid affects FAO activity. [source] Peroxisome proliferator-activated receptor alpha and the ketogenic dietEPILEPSIA, Issue 2008Tim Cullingford Summary Peroxisome proliferator-activated receptor alpha (PPAR,) is a drug/fatty acid-activated trans cription factor involved in the starvation response, and is thus relevant to the ketogenic diet (KD). This article summarizes research indicating the role of PPAR, in central and peripheral nervous system function with particular reference to downstream targets relevant to anticonvulsant action. [source] The PPAR, agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibitionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2007T. Kino Abstract Background, Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor , (PPAR,), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. Materials and methods, We examined the ability of the synthetic PPAR, agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results, GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein ,1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of ,2-acid glycoprotein, ,-fibrinogen and ,2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPAR, receptor, but not of PPAR, or ,, attenuated the suppressive effect of GW501516 on interleukin-6-induced ,1-antichymotrypsin mRNA expression, indicating that PPAR, specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the ,1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPAR, on this promoter. Overexpression of PPAR, enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the ,1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. Conclusions, These findings indicate that agonist-activated PPAR, interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPAR, agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role. [source] Fatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded heartsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2004T. Miyamoto Abstract Background, The peroxisome proliferator-activated receptor (PPAR) , is a member of the nuclear receptor superfamily and regulates gene expression of fatty acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure-overload, myocardial energy utilization reverts to the fetal pattern, and metabolic substrate switches from fatty acid to glucose. However, myocardial metabolism in volume-overloaded hearts has not been rigorously studied. The aim of the present study was to examine fatty acid metabolism and protein expressions of PPAR, and fatty acid oxidation enzymes in volume-overloaded rabbit hearts. Methods, Volume-overload was induced by carotid-jugular shunt formation. Sham-operated rabbits were used as control. Chronic volume-overload increased left ventricular weight and ventricular cavity size, and relative wall thickness was decreased, indicating eccentric cardiac hypertrophy. 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) was intravenously administered, and animals were sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to iodophenyl-3-methylnonanoic acid (3MNA) by ,-oxidation. Lipid extraction from the myocardium was performed by the Folch method, and radioactivity distribution of metabolites was assayed by thin-layer chromatography. The protein was extracted from the left ventricular myocardium, and levels of PPAR, and fatty acid oxidation enzymes were examined by Western blotting. Results, Myocardial distribution of 9MPA tended to be more heterogeneous in shunt than in sham rabbits (P = 0·06). In volume-overloaded hearts by shunt, the conversion from 9MPA to 3MNA by ,-oxidation was faster than the sham-control hearts (P < 0·05). However, protein levels of PPAR, and fatty acid utilization enzymes were unchanged in shunt rabbits compared with sham rabbits. Conclusions, These data suggest that myocardial fatty acid metabolism is enhanced in eccentric cardiac hypertrophy by volume-overload without changes in protein expressions of PPAR, and fatty acid utilization enzymes. Our data may provide a novel insight into the subcellular mechanisms for the pathological process of cardiac remodelling in response to mechanical stimuli. [source] PRECLINICAL STUDY: FULL ARTICLE: Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-, nuclear receptorsADDICTION BIOLOGY, Issue 3 2010Antonio Luchicchi ABSTRACT The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system. [source] PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2009Nicoletta Schintu Abstract Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-,). PPAR-, can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-, agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted. [source] Sodium lauryl sulphate alters the mRNA expression of lipid-metabolizing enzymes and PPAR signalling in normal human skin in vivoEXPERIMENTAL DERMATOLOGY, Issue 12 2009Hans Törmä Abstract:, Detergents irritate skin and affect skin barrier homeostasis. In this study, healthy skin was exposed to 1% sodium lauryl sulphate (SLS) in water for 24 h. Biopsies were taken 6 h to 8 days post exposure. Lipid patterns were stained in situ and real-time polymerase chain reaction (PCR) was used to examine mRNA expression of enzymes synthesizing barrier lipids, peroxisome proliferator-activated receptors (PPAR) and lipoxygenases. The lipid pattern was disorganized from 6 h to 3 days after SLS exposure. Concomitant changes in mRNA expression included: (i) reduction, followed by induction, of ceramide-generating ,-glucocerebrosidase, (ii) increase on day 1 of two other enzymes for ceramide biosynthesis and (iii) persistent reduction of acetyl-CoA carboxylase-B, a key enzyme in fatty acid synthesis. Surprisingly, the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase, was unaltered. Among putative regulators of barrier lipids synthesis, PPAR, and PPAR, exhibited reduced mRNA expression, while PPAR,/, and LXR, were unaltered. Epidermal lipoxygenase-3, which may generate PPAR, agonists, exhibited reduced expression. In conclusion, SLS induces reorganization of lipids in the stratum corneum, which play a role in detergents' destruction of the barrier. The changes in mRNA expression of enzymes involved in synthesizing barrier lipids are probably important for the restoration of the barrier. [source] Phospholipase stimulates lipogenesis in SZ95 sebocytesEXPERIMENTAL DERMATOLOGY, Issue 7 2008S. Schagen Introduction:, With progressing ageing human sebocytes reduce lipid production. However, the influence of certain aging mechanisms on sebaceous lipid synthesis as well as ways to influence the latter is not fully identified. Certain lipids act as ligands of nuclear receptors such as PPAR. Phospholipase (PLA2) catalyzes the hydrolysis of the sn-2 fatty acyl bond of phospholipids to yield free fatty acid and lysophospholipid. It has been hypothesized that PPAR may be activated by hydrolysis products of phospholipids and also by eicosanoids obtained through PLA2 activity. Materials and Methods:, A method to quantify sebaceous lipid synthesis of SZ95 sebocytes in vitro was established and the cells were treated by snake venom Bothrops moojeni gel filtration fractions (Botmo GF). Botmo GF fractions were further purified by RP-HPLC, and a fraction with PLA2 activity (Botmo GF11-117) and a fraction without enzymatic activity (Botmo GF11-101) were identified and additionally tested. Results:, Botmo GF fractions increased lipogenesis in SZ95 sebocytes without inducing apparent toxic or apoptotic effects. Botmo GF11-101 (1 ,g/ml) enhanced neutral lipid synthesis by up to 170% and polar lipid synthesis by up to 120%. The enzymatically active PLA2 Botmo GF11-117 (1 ,g/ml) increased synthesis of neutral lipids by up to 200%, and polar lipids by up to 120% compared to untreated SZ95 sebocytes. Conclusion:, PLA2 activation or suppression could be important for human sebaceous lipogenesis. PLA2 modifiers may be attractive for skin lipid research and pharmacological/cosmetic products. [source] Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-,, normalizes epidermal homeostasis in a murine hyperproliferative disease modelEXPERIMENTAL DERMATOLOGY, Issue 3 2006Marianne Demerjian Abstract:, In a murine model of epidermal hyperplasia reproducing some of the abnormalities of several common skin disorders, we previously demonstrated the antiproliferative and pro-differentiating effects of peroxisome proliferator-activated receptor (PPAR),, PPAR,/,, and liver X receptor activators. Unlike other subgroups of PPAR activators, thiazolidinediones (TZDs), a family of PPAR, ligands, did not inhibit keratinocyte proliferation in normal murine skin. Here, we studied the effects of two TZDs, namely ciglitazone (10 mM) and troglitazone (1 mM), in the same murine model where epidermal hyperproliferation was reproduced by repeated barrier abrogation with tape stripping. Topical treatment with ciglitazone and troglitazone resulted in a marked and significant decrease in epidermal thickness. Furthermore, in all TZD-treated groups, we observed a significant decrease in keratinocyte proliferation using proliferating cell nuclear antigen, 5-bromo-2,-deoxyuridine, and tritiated thymidine incorporation. However, using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found no difference in apoptosis between different treatments, emphasizing that it is the antiproliferative role of these activators that accounts for the decrease of epidermal thickness. Finally, using immunohistochemical methods, we determined the effects of ciglitazone on keratinocyte differentiation in this hyperproliferative model. We observed an increased expression of involucrin and filaggrin following ciglitazone treatment, suggesting a pro-differentiating action of TZDs in this model. In summary, topical TZDs significantly reduce epidermal keratinocyte proliferation while promoting differentiation in a murine model of hyperproliferative epidermis. Together, these results suggest that in addition to their metabolic effects currently in use in the treatment of type 2 diabetes, topical TZDs could be considered as potential alternative therapeutic agents in hyperproliferative skin diseases such as psoriasis. [source] Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-, signaling inhibition of proliferation of rat pulmonary artery smooth muscle cellsFEBS JOURNAL, Issue 6 2010Manxiang Li Activation of peroxisome proliferator-activated receptor (PPAR)-, suppresses proliferation of rat pulmonary artery smooth muscle cells (PASMCs), and therefore ameliorates the development of pulmonary hypertension in animal models. However, the molecular mechanisms underlying this effect remain largely unknown. This study addressed this issue. The PPAR, agonist rosiglitazone dose-dependently stimulated heme oxygenase (HO)-1 expression in PASMCs, 5 ,m rosiglitazone inducing a 12.1-fold increase in the HO-1 protein level. Cells pre-exposed to rosiglitazone showed a dose-dependent reduction in proliferation in response to serotonin; this was abolished by pretransfection of cells with sequence-specific small interfering RNA against HO-1. In addition, rosiglitazone stimulated p21WAF1 expression in PASMCs, a 2.34-fold increase in the p21WAF1 protein level being achieved with 5 ,m rosiglitazone; again, this effect was blocked by knockdown of HO-1. Like loss of HO-1, loss of p21WAF1 through siRNA transfection also reversed the inhibitory effect of rosiglitazone on PASMC proliferation triggered by serotonin. Taken together, our findings suggest that activation of PPAR, induces HO-1 expression, and that this in turn stimulates p21WAF1 expression to suppress PASMC proliferation. Our study also indicates that rosiglitazone, a medicine widely used in the treatment of type 2 diabetes mellitus, has potential benefits for patients with pulmonary hypertension. [source] 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-,-dependent and mediated by the caspase-3-dependent apoptotic pathwayFEBS JOURNAL, Issue 3 2010Yuanyuan Xiao Although thiazolidinediones (TZDs) are potent promoters of adipogenesis in the preadipocyte, they induce apoptosis in several other cell types, such as cancer cells, endothelial cells and T-lymphocytes. In this study, we investigated the proapoptotic effect of TZDs in mature 3T3-L1 adipocytes, which express high levels of the peroxisome proliferator-activated receptor-, (PPAR,) protein. Apoptosis was induced in mature 3T3-L1 adipocytes by treatment with troglitazone, pioglitazone or prostaglandin J2, and could be blocked by the PPAR, antagonist GW9662. Treatment with PPAR, agonists also decreased Akt-1 protein and phosphorylation levels without affecting phosphoinositide 3-kinase and PTEN. Further analysis indicated that in troglitazone-treated 3T3-L1 adipocytes, Bad phosphorylation and Bcl-2 protein levels were reduced, and Bax translocation to the mitochondria was increased. Subsequently, cytochrome c release and caspase-3 cleavage were observed. TZD-induced adipocyte apoptosis could be blocked by the caspase-3 inhibitor Ac-DEVD-CHO or by overexpression of Bcl2. In cultured rat primary adipocytes, similar apoptosis-inducing effects of troglitazone were also observed. Thus, TZDs promote apoptosis in adipocytes through a PPAR,-dependent pathway. This apoptosis is mediated by the inhibition of Akt-1, which decreases Bad phosphorylation and activates the mitochondrial apoptotic pathway. [source] Role of ceramide kinase in peroxisome proliferator-activated receptor beta-induced cell survival of mouse keratinocytesFEBS JOURNAL, Issue 15 2008Kiyomi Tsuji Ceramide (Cer) is known to be a lipid mediator in apoptosis and to have an important role in cell fate, via control of intracellular Cer levels. Recently, ceramide kinase (CerK) was identified as an enzyme that converts Cer to ceramide 1-phosphate (C1P). We examined potential functions of CerK in the regulation of keratinocyte survival, and the possible involvement of peroxisome proliferator-activated receptor beta (PPAR,). PPAR, is known to be a nuclear receptor acting as a ligand-inducible transcription factor and has been implicated in the control of keratinocyte survival. In the mouse keratinocyte cell line SP1, serum starvation induced cell death and the accumulation of intracellular Cer, an apoptotic event. However, apoptosis was inhibited by activation of PPAR,. Interestingly, activation of PPAR, enhanced the mRNA expression of CerK and CerK activity. Furthermore, the cell survival effect of PPAR, was greatly diminished in keratinocytes isolated from CerK-null mice. Chromatin immunoprecipitation revealed that, in vivo, PPAR, binds to the CerK gene via a sequence located in the first intron. Electrophoretic mobility-shift assays confirmed that PPAR, associates with this sequence in vitro. These findings indicated that CerK gene expression was directly regulated by PPAR,. In conclusion, our results demonstrate that PPAR,-mediated upregulation of CerK gene expression is necessary for keratinocyte survival against serum starvation-induced apoptosis. [source] Peroxisome proliferator-activated receptor ,,retinoid X receptor agonists induce beta-cell protection against palmitate toxicityFEBS JOURNAL, Issue 23 2007Karine Hellemans Fatty acids can stimulate the secretory activity of insulin-producing beta-cells. At elevated concentrations, they can also be toxic to isolated beta-cells. This toxicity varies inversely with the cellular ability to accumulate neutral lipids in the cytoplasm. To further examine whether cytoprotection can be achieved by decreasing cytoplasmic levels of free acyl moieties, we investigated whether palmitate toxicity is also lowered by stimulating its ,-oxidation. Lower rates of palmitate-induced beta-cell death were measured in the presence of l -carnitine as well as after addition of peroxisome proliferator-activated receptor , (PPAR,) agonists, conditions leading to increased palmitate oxidation. In contrast, inhibition of mitochondrial ,-oxidation by etomoxir increased palmitate toxicity. A combination of PPAR, and retinoid X receptor (RXR) agonists acted synergistically and led to complete protection; this was associated with enhanced expression levels of genes involved in mitochondrial and peroxisomal ,-oxidation, lipid metabolism, and peroxisome proliferation. PPAR,,RXR protection was abolished by the carnitine palmitoyl transferase 1 inhibitor etomoxir. These observations indicate that PPAR, and RXR regulate beta-cell susceptibility to long-chain fatty acid toxicity by increasing the rates of ,-oxidation and by involving peroxisomes in fatty acid metabolism. [source] Regulated expression by PPAR, and unique localization of 17,-hydroxysteroid dehydrogenase type 11 protein in mouse intestine and liverFEBS JOURNAL, Issue 18 2007Yasuhide Yokoi 17,-Hydroxysteroid dehydrogenase type 11 (17,-HSD11) is a member of the short-chain dehydrogenase/reductase family involved in the activation and inactivation of sex steroid hormones. We recently identified 17,-HSD11 as a gene that is efficiently regulated by peroxisome proliferator-activated receptor-, PPAR, in the intestine and the liver [Motojima K (2004) Eur J Biochem271, 4141,4146]. In this study, we characterized 17,-HSD11 at the protein level to obtain information about its physiologic role in the intestine and liver. For this purpose, specific antibodies against 17,-HSD11 were obtained. Western blotting analysis showed that administration of a peroxisome proliferator-activated receptor-, agonist induced 17,-HSD11 protein in the jejunum but not in the colon, and to a much higher extent than in the liver of mice. A subcellular localization study using Chinese hamster ovary cells and green fluorescent protein-tagged 17,-HSD11 showed that it was mostly localized in the endoplasmic reticulum under normal conditions, whereas it was concentrated on lipid droplets when they were induced. A pulse-chase experiment suggested that 17,-HSD11 was redistributed to the lipid droplets via the endoplasmic reticulum. Immunohistochemical analysis using tissue sections showed that 17,-HSD11 was induced mostly in intestinal epithelia and hepatocytes, with heterogeneous localization both in the cytoplasm and in vesicular structures. A subcellular fractionation study of liver homogenates confirmed that 17,-HSD11 was localized mostly in the endoplasmic reticulum when mice were fed a normal diet, but was distributed in both the endoplasmic reticulum and the lipid droplets of which formation was induced by feeding a diet containing a proliferator-activated receptor-, agonist. Taken together, these data indicate that 17,-HSD11 localizes both in the endoplasmic reticulum and in lipid droplets, depending on physiologic conditions, and that lipid droplet 17,-HSD11 is not merely an endoplasmic reticulum contaminant or a nonphysiologically associated protein in the cultured cells, but a bona fide protein component of the membranes of both intracellular compartments. [source] Identification of ERR, as a specific partner of PGC-1, for the activation of PDK4 gene expression in muscleFEBS JOURNAL, Issue 8 2006Makoto Araki Pyruvate dehydrogenase kinase 4 (PDK4) is a key regulatory enzyme involved in switching the energy source from glucose to fatty acids in response to physiological conditions. Transcription of the PDK4 gene is activated by fasting or by the administration of a PPAR, ligand in a tissue-specific manner. Here, we show that the two mechanisms are independent, and that ERR, is directly involved in PPAR,-independent transcriptional activation of the PDK4 gene with PGC-1, as a specific partner. This conclusion is based on the following evidence. First, detailed mutation analyses of the cloned PDK4 gene promoter sequence identified a possible ERR,-binding motif as the PGC-1, responsive element. Second, overexpression of ERR, by cotransfection enhanced, and the knockout of it by shRNAs diminished, PGC-1,-dependent activation. Third, specific binding of ERR, to the identified PGC-1, responsive sequence was confirmed by the electrophoresis mobility shift assay. Finally, cell-type-specific responsiveness to PGC-1, was observed and this could be explained by differences in the expression levels of ERR,, however, ectopic expression of ERR, in poorly responsive cells did not restore PGC-1, responsiveness, indicating that ERR, is necessary, but not sufficient for the response. [source] 15-Deoxy ,12,14 -prostaglandin J2 suppresses transcription by promoter 3 of the human thromboxane A2 receptor gene through peroxisome proliferator-activated receptor , in human erythroleukemia cellsFEBS JOURNAL, Issue 18 2005Adrian T. Coyle In humans, thromboxane (TX) A2 signals through two receptor isoforms, thromboxane receptor (TP), and TP,, which are transcriptionally regulated by distinct promoters, Prm1 and Prm3, respectively, within the single TP gene. The aim of the current study was to investigate the ability of the endogenous peroxisome proliferator-activated receptor (PPAR), ligand 15-deoxy-,12,14 -prostaglandin J2 (15d-PGJ2) to regulate expression of the human TP gene and to ascertain its potential effects on the individual TP, and TP, isoforms. 15d-PGJ2 suppressed Prm3 transcriptional activity and TP, mRNA expression in the platelet progenitor megakaryocytic human erythroleukemia (HEL) 92.1.7 cell line but had no effect on Prm1 or Prm2 activity or on TP, mRNA expression. 15d-PGJ2 also resulted in reductions in the overall level of TP protein expression and TP-mediated intracellular calcium mobilization in HEL cells. 15d-PGJ2 suppression of Prm3 transcriptional activity and TP, mRNA expression was found to occur through a novel mechanism involving direct binding of PPAR,,retinoic acid X receptor (RXR) heterodimers to a PPAR, response element (PPRE) composed of two imperfect hexameric direct repeat (DR) sequences centred at ,159 and ,148, respectively, spaced by five nucleotides (DR5). These data provide direct evidence for the role of PPAR, in the regulation of human TP gene expression within the vasculature and point to further critical differences in the modes of transcriptional regulation of TP, and TP, in humans. Moreover, these data highlight a further link between enhanced risk of cardiovascular disease in diabetes mellitus associated with increased synthesis and action of thromboxane A2 (TXA2). [source] Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2)FEBS JOURNAL, Issue 12 2001Promoter analysis, role of the peroxisome proliferator-activated receptor PPAR X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease due to a defect in the ABCD1 (ALD) gene. ABCD1, and the two close homologues ABCD2 (ALDR) and ABCD3 (PMP70), are genes encoding ATP-binding cassette half-transporters of the peroxisomal membrane. As overexpression of the ABCD2 or ABCD3 gene can reverse the biochemical phenotype of X-ALD (reduced ,-oxidation of very-long-chain fatty acids), pharmacological induction of these partially redundant genes may represent a therapeutic approach to X-ALD. We previously reported that the ABCD2 and ABCD3 genes could be strongly induced by fibrates, which are hypolipidaemic drugs and peroxisome-proliferators in rodents. We provide evidence that the induction is dependent on peroxisome proliferator-activated receptor (PPAR,) as both genes were not induced in fenofibrate-treated PPAR,,/, knock-out mice. To further characterize the PPAR, pathway, we cloned and analysed the promoter of the ABCD2 gene, the closest homologue of the ABCD1 gene. The proximal region (2 kb) of the rat promoter displayed a high conservation with the human and mouse cognate sequences suggesting an important role of the region in regulation of the ABCD2 gene. Classically, fibrate-induction involves interaction of PPAR, with a response element (PPRE) characterized by a direct repeat of the AGGTCA-like motif. Putative PPRE motifs of the rat ABCD2 promoter were studied in the isolated form or in their promoter context by gel-shift assay and transfection of COS-7 cells. We failed to characterize a functional PPRE, suggesting a different mechanism for the PPAR,-dependent regulation of the ABCD2 gene. [source] Phytanoyl-CoA hydroxylase activity is induced by phytanic acidFEBS JOURNAL, Issue 13 2000Anna W. M. Zomer Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid present in various dietary products such as milk, cheese and fish. In patients with Refsum disease, accumulation of phytanic acid occurs due to a deficiency of phytanoyl-CoA hydroxylase, a peroxisomal enzyme containing a peroxisomal targeting signal 2. Recently, phytanoyl-CoA hydroxylase cDNA has been isolated and functional mutations have been identified. As it has been shown that phytanic acid activates the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR), and all three retinoid X receptors (RXRs), the intracellular concentration of this fatty acid should be tightly regulated. When various cell lines were grown in the presence of phytanic acid, the activity of phytanoyl-CoA hydroxylase increased up to four times, depending on the particular cell type. In one cell line, HepG2, no induction of phytanoyl-CoA hydroxylase activity was observed. After addition of phytanic acid to COS-1 cells, an increase in phytanoyl-CoA hydroxylase activity was observed within 2 h, indicating a quick cell response. No stimulation of phytanoyl-CoA hydroxylase was observed when COS-1 cells were grown in the presence of clofibric acid, 9- cis -retinoic acid or both ligands together. This indicates that the activation of phytanoyl-CoA hydroxylase is not regulated via PPAR, or RXR. However, stimulation of PPAR, and all RXRs by clofibric acid and 9- cis -retinoic acid was observed in transient transfection assays. These results suggest that the induction of phytanoyl-CoA hydroxylase by phytanic acid does not proceed via one of the nuclear hormone receptors, RXR or PPAR,. [source] Regulation of inflammation by PPARs: a future approach to treat lung inflammatory diseases?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2006Julien Becker Abstract Lung inflammatory diseases, such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis, represent a major health problem worldwide. Although glucocorticoids are the most potent anti-inflammatory drug in asthma, they exhibit major side effects and have poor activity in lung inflammatory disorders such as ALI or COPD. Therefore, there is growing need for the development of alternative or new therapies to treat inflammation in the lung. Peroxisome proliferator-activated receptors (PPARs), including the three isotypes PPAR,, PPAR, (or PPAR,) and PPAR,, are transcription factors belonging to the nuclear hormone receptor superfamily. PPARs, and in particular PPAR, and PPAR,, are well known for their critical role in the regulation of energy homeostasis by controlling expression of a variety of genes involved in lipid and carbohydrate metabolism. Synthetic ligands of the two receptor isotypes, the fibrates and the thiazolidinediones, are clinically used to treat dyslipidaemia and type 2 diabetes, respectively. Recently however, PPAR, and PPAR, have been shown to exert a potent anti-inflammatory activity, mainly through their ability to downregulate pro-inflammatory gene expression and inflammatory cell functions. The present article reviews the current knowledge of the role of PPAR, and PPAR, in controlling inflammation, and presents different findings suggesting that PPAR, and PPAR, activators may be helpful in the treatment of lung inflammatory diseases. [source] Multiple roles of PPAR, in brown adipose tissue under constitutive and cold conditionsGENES TO CELLS, Issue 2 2010Makiko Komatsu Peroxisome proliferator-activated receptor , (PPAR,) is a member of the nuclear receptor family, regulating fatty acid degradation in many organs. Two-dimensional SDS-PAGE of brown adipose tissue (BAT) from PPAR,-null mice produced a higher-density spot. Proteomic analysis indicated that the protein was pyruvate dehydrogenase , (PDH,). To observe PDH, regulation in BAT, the organ was stimulated by long-term cold exposure, and the activities of associated enzymes were investigated. Histological and biochemical analyses of BAT showed a significant decrease in the triglyceride content in wild-type mice and some degree of decrease in PPAR,-null mice on cold exposure. Analyses of molecules related to glucose metabolism showed that the expression of PDH, is under PPAR,-specific regulation, and that glucose degradation ability may decrease on cold exposure. In contrast, analyses of molecules related to fatty acid metabolism showed that numerous PPAR,/, target molecules are induced on cold exposure, and that fatty acid degradation ability in wild-type mice is markedly enhanced and also increases to same degree in PPAR,-null mice on cold exposure. Thus, this study proposes novel and multiple roles of PPAR, in BAT. [source] | |||||||||||||||||||||||||||||||||||||