Gene Expression Of Peroxisome Proliferator-activated Receptor Research Articles

Developmental exposures to perfluorooctanesulfonic acid (PFOS) impact embryonic nutrition, pancreatic morphology, and adiposity in the zebrafish, Danio rerio.

Perfluorooctanesulfonic acid (PFOS) is a persistent environmental contaminant previously found in consumer surfactants and industrial fire-fighting foams. PFOS has been widely implicated in metabolic dysfunction across the lifespan, including diabetes and obesity. However, the contributions of the embryonic environment to metabolic disease remain uncharacterized. This study seeks to identify perturbations in embryonic metabolism, pancreas development, and adiposity due to developmental and subchronic PFOS exposures and their persistence into later larval and juvenile periods. Zebrafish embryos were exposed to 16 or 32μM PFOS developmentally (1-5 days post fertilization; dpf) or subchronically (1-15 dpf). Embryonic fatty acid and macronutrient concentrations and expression of peroxisome proliferator-activated receptor (PPAR) isoforms were quantified in embryos. Pancreatic islet morphometry was assessed at 15 and 30 dpf, and adiposity and fish behavior were assessed at 15 dpf. Concentrations of lauric (C12:0) and myristic (C14:0) saturated fatty acids were increased by PFOS at 4 dpf, and PPAR gene expression was reduced. Incidence of aberrant islet morphologies, principal islet areas, and adiposity were increased in 15 dpf larvae and 30 dpf juvenile fish. Together, these data suggest that the embryonic period is a susceptible window of metabolic programming in response to PFOS exposures, and that these early exposures alone can have persisting effects later in the lifecourse.

The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases, including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet little is known about the interactions between genetic and transcriptional events of pathway genes in a pan-cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 genes demonstrating mutually exclusive patterns of loss- and gain-of-function phenotypes. These genes successfully predicted patient survival rates in bladder, renal, glioma, liver, and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically relevant relationships between PPARs and hypoxia were observed, where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity, and hypoxia.

Effects of tetramethylpyrazine from Chinese black vinegar on antioxidant and hypolipidemia activities in HepG2 cells

Tetramethylpyrazine is a bioactive compound found in Chinese black vinegar. This work is to investigate the potential effects of tetramethylpyrazine on intracellular cholesterol modulation in HepG2 cells. The results demonstrated that tetramethylpyrazine can induce intracellular cholesterol efflux. Tetramethylpyrazine may also improve endothelial function through its antioxidant effects by inhibiting reactive oxygen species levels and increasing the antioxidant enzymes superoxide dismutase and catalase. Tetramethylpyrazine increased liver X receptor and peroxisome proliferator-activated receptor gene expression in HepG2 cells. Protein expression of ATP-binding cassette transporter 1 was up-regulated in a dose-dependent manner (P < 0.05). The biological significance of tetramethylpyrazine may involve hypolipidemic effects via modulation of intracellular cholesterol efflux, ROS inhibition, increases in SOD and CAT activities, and direct regulation of PPAR and LXR gene expression. Tetramethylpyrazine may improve lipid profiles by elevating the PPARγ-LXRα-ABCA1 pathway.

Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis.

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δ mRNA (p = 0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p = 0.026 and p = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.

MP34-13 PPAR-α/γ AGONISTS HAVE DIFFERENT EFFECTS ON RENAL CRYSTAL FORMATION IN HYPEROXALURIC ANIMAL MODELS

You have accessJournal of UrologyStone Disease: Basic Research II1 Apr 2015MP34-13 PPAR-α/γ AGONISTS HAVE DIFFERENT EFFECTS ON RENAL CRYSTAL FORMATION IN HYPEROXALURIC ANIMAL MODELS Kazumi Taguchi, Rei Unno, Yasuhiro Hirose, Shuzo Hamamoto, Takahiro Kobayashi, Ryosuke Ando, Atsushi Okada, Yasunori Itoh, Takahiro Yasui, Keiichi Tozawa, Yutaro Hayashi, and Kenjiro Kohri Kazumi TaguchiKazumi Taguchi More articles by this author , Rei UnnoRei Unno More articles by this author , Yasuhiro HiroseYasuhiro Hirose More articles by this author , Shuzo HamamotoShuzo Hamamoto More articles by this author , Takahiro KobayashiTakahiro Kobayashi More articles by this author , Ryosuke AndoRyosuke Ando More articles by this author , Atsushi OkadaAtsushi Okada More articles by this author , Yasunori ItohYasunori Itoh More articles by this author , Takahiro YasuiTakahiro Yasui More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , Yutaro HayashiYutaro Hayashi More articles by this author , and Kenjiro KohriKenjiro Kohri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1309AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urolithiasis has inflammatory and oxidative stress-related characteristics resembling metabolic syndrome (Mets). No therapy targeting the molecular biology of crystal formation has been developed, although statins and peroxisome proliferator-activated receptor (PPAR) agonists are used to treat Mets. Hence, we evaluated the in vivo efficacy of PPAR agonists for preventing renal crystal formation and investigated changes in gene expression of PPARs and related inflammatory and oxidative molecules in a hyperoxaluric animal model. METHODS We first examined PPAR gene expression by microarray analysis of a mouse kidney stone model in which hyperoxaluria was induced by daily intra-abdominal glyoxylate injection. Affymetrix GeneSpring GX11.0 was used with unbiased gene expression profiling to investigate global renal gene expression. Then, we investigated the effects of 3 different PPAR agonists, the PPARα agonists bezafibrate (BZF) and fenofibrate (FF), and the PPARγ agonist pioglitazone (PGZ). SD rats were untreated (Ctl) or treated with 1% ethylene glycol (EG), 1% EG and 30 mg/kg BZF (EG + B), 1% EG and 30 mg/kg FF (EG + F), or 1% EG and 10 mg/kg PGZ (EG + P). Blood and 24-h urine samples and kidney sections were collected after 14 days□f treatment. We examined crystal formation using Pizzolato staining and polarized light optical microscopy and evaluated inflammation, cell injury, apoptosis, and oxidative stress with immunohistochemistry and quantitative polymerase chain reaction. RESULTS Microarray analysis showed increased PPARγ expression after crystal formation but no change in PPARα expression during crystal formation. Renal crystal formation was significantly lower in the EG + P and higher in the EG + B and EG + F groups than in the EG group (Figure). The serum and urinary levels of Ca, P, and Mg and urinary level of oxalate did not differ among the EG + B, EG + F, and EG + P groups. PGZ administration markedly decreased cell injury, apoptosis, and oxidative stress. Administration of both BZF and FF increased serum levels of creatinine that caused glomerulotubular injury. CONCLUSIONS PPAR-α agonists suppresses renal crystal formation via its renal tubular cytoprotective effects whereas PPAR-α agonists accelerate crystal formation via its renal toxicity. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e415 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazumi Taguchi More articles by this author Rei Unno More articles by this author Yasuhiro Hirose More articles by this author Shuzo Hamamoto More articles by this author Takahiro Kobayashi More articles by this author Ryosuke Ando More articles by this author Atsushi Okada More articles by this author Yasunori Itoh More articles by this author Takahiro Yasui More articles by this author Keiichi Tozawa More articles by this author Yutaro Hayashi More articles by this author Kenjiro Kohri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prenatal polycyclic aromatic hydrocarbon, adiposity, peroxisome proliferator-activated receptor (PPAR) γ methylation in offspring, grand-offspring mice.

RationaleGreater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH) have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear.ObjectivesWe hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected.Materials and MethodsPregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND) 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding proteins (C/EBP) α, cyclooxygenase (Cox)-2, fatty acid synthase (FAS) and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue.FindingsOffspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice.ConclusionsGreater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

Genetics of cardiovascular disorders: influence of maternal nutrition.

Cardiovascular disease (CVD) is the number one non-communicable disease of the world. According to the World Health Organization, 30% of global deaths in 2008 were caused by CVD, and it is estimated that by 2030, more than 23 million people will die annually from CVD. Unfortunately, India will be the leading country of the world to have the highest rate of CVD by 2030. Genetics, as well as diet and life style are the predominant factors predisposing the population to an increased risk of CVD. Although genetic makeup is generally considered as the culprit, recent phenomenon of “Developmental origins of health and diseases” or “in-utero programming” places significant importance on maternal diet in predisposing the next generation to metabolic disorders. According to this phenomenon, the diet of the mother during gestation and lactation affects the genetic makeup of the growing foetus, thereby causing perturbations in the metabolic regulations of the offspring, and later onset of diseases. Dietary fats are known to be associated with an increased risk of CVD; however the importance of maternal dietary fats in “in-utero programming” and the onset of CVD in the offspring in later life is not clear. We have shown that a maternal diet high in saturated fatty acids (SFA) increased the levels of low-density lipoprotein (LDL) cholesterol of the offspring by inhibiting hepatic LDL-receptor gene expression. Furthermore, maternal high fat diets caused aortic endothelial dysfunction, which is an additional factor associated with CVD. High fat diets during gestation and lactation also induce fatty liver and myocardium hypertrophy, due to inhibition of beta-oxidation through peroxisome proliferator activated receptors (PPARs). We found that maternal high fat diets altered the gene expression of PPARs, which likely involves epigenetic modifications. On the other hand, we found that maternal diets high in omega (n)-3 PUFA reduced plasma lipid levels of the offspring, thereby reducing the risk of CVD. Our findings have established the importance of maternal dietary fat intake during gestation and lactation to prevent the onset of CVD in the next generation. The Indian population is predisposed to an increased risk of CVD due to their genetic makeup. It is therefore recommended that the Indian population, especially women in their child bearing years, should manage the intake of dietary fat- both the quantity and the quality, to prevent the onset of CVD and other metabolic disorders in the next generation.

Hypolipidemic effect of Goami-3 rice (Oryza sativa L. cv. Goami-3) on C57BL/6J mice is mediated by the regulation of peroxisome proliferator-activated receptor-α and -γ

We investigated the hypolipidemic effects of Goami-3 rice (GR; Oryza sativa L. cv. Goami-3), a newly developed strain with high levels of amylose and fibers. Diet-induced obese mice were fed three types of isocaloric diets for 8weeks: a high-fat diet, a high-fat diet with GR or control rice (CR; O. sativa L. cv. Ilpumbyeo). Mice fed GR exhibited a significant reduction in body fat (–23%), total cholesterol (–20%) and triglyceride concentrations (–30%) compared to mice fed CR. The mice fed GR showed induction of peroxisome proliferator-activated receptor (PPAR)-α and inhibition of γ expressions in the liver and adipose tissue. The reduced adiposity of mice fed GC was supported by changes in the expression of genes related to lipid accumulation and hydrolysis in adipose tissues and the plasma concentrations of insulin, adiponectin and leptin. Principal components analysis with gas chromatography–time-of-flight mass spectrometry-based metabolomic data revealed that the average level of specific plasma metabolites in the GR group was statistically different from that in the other groups after 4weeks. These metabolites included propionic acid, valine, leucine and proline. Based on partial least-squares analysis, the plasma concentrations of valine were inversely correlated with the high-density lipoprotein (HDL) to non-HDL and HDL to total cholesterol ratios. In conclusion, GR feeding for 8weeks significantly improved dyslipidemia and adiposity in diet-induced obese mice by regulating gene expression of PPARs and its target genes. Key plasma metabolites (including valine) were significantly altered by the hypolipidemic effects of GR.

Omega 3 polyunsaturated fatty acid improves spatial learning and hippocampal Peroxisome Proliferator Activated Receptors (PPARα and PPARγ) gene expression in rats

BackgroundThis study examined the effects of dietary polyunsaturated fatty acids (PUFA) as different n-6: n-3 ratios on spatial learning and gene expression of peroxisome- proliferator-activated receptors (PPARs) in the hippocampus of rats. Thirty male Sprague–Dawley rats were randomly allotted into 3 groups of ten animals each and received experimental diets with different n-6: n-3 PUFA ratios of either 65:1, 22:1 or 4.5:1. After 10 weeks, the spatial memory of the animals was assessed using the Morris Water Maze test. The expression of PPARα and PPARγ genes were determined using real-time PCR.ResultsDecreasing dietary n-6: n-3 PUFA ratios improved the cognitive performance of animals in the Morris water maze test along with the upregulation of PPARα and PPARγ gene expression. The animals with the lowest dietary n-6: n-3 PUFA ratio presented the highest spatial learning improvement and PPAR gene expression.ConclusionIt can be concluded that modulation of n-6: n-3 PUFA ratios in the diet may lead to increased hippocampal PPAR gene expression and consequently improved spatial learning and memory in rats.

T.P.37 Changes in muscle expression of PGC-1α and related signalling molecules in the mdx mouse: Possible impact on adaptive fiber phenotype transition and implication for drug studies

<h2>Abstract</h2> In Duchenne muscular dystrophy (DMD), the absence of dystrophin causes a complex pathogenetic cascade also involving sarcolemmal fragility and metabolic distress. Increasing evidences in mdx mouse model outline the potential interest of therapeutic strategies to reinforce pathways leading to activation of peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α), a key modulator of oxidative metabolism and mitochondrial biogenesis. Accordingly, we recently found beneficial effects of resveratrol, a PGC-1α activator via sirtuin 1 (Sirt1), in exercised mdx mice. To better understand the basal regulation of this mechano-sensitive metabolic pathway in dystrophic skeletal muscle we performed real-time PCR experiments in gastrocnemius (GC) muscles of mdx mice at different ages. We found slightly higher levels of PGC-1α mRNA in mdx mice of 8weeks of age vs. age-matched C57BL/10 (wt) mice. The increase in PGC-1α became highly significant at 16weeks of age and was paralleled by a 40% rise in Sirt1 mRNA. Focusing on 16weeks of age, we then assessed the gene expression of PPARs since PGC-1α cooperates with members of this receptor family to regulate expression of mitochondrial and β-oxidation enzymes. Interestingly, the expression of PPAR-δ was markedly higher in mdx GC muscle vs. wt one, while PPAR-γ had a comparable expression in the two genotypes. Afterwards the impact of the above changes on phenotype and glycolytic/oxidative metabolism of dystrophic muscle has been evaluated on genes expression of myosin heavy chain (MHC) isoforms. A significant increase of slow-oxidative type I MHC and a decrease of fast-glycolytic IIb MHC were found in mdx GC muscle vs. wt ones. Then a modification of PGC-1α pathway, which likely triggers a protective slow-oxidative myofiber program, naturally occurs in the mdx mouse muscle and may modulate the outcome of physiological stimuli and of pharmacological strategies (Supported by Duchenne Parent Project NL).

High multivitamin intakes during pregnancy and postweaning obesogenic diets interact to affect the relationship between expression of PPAR genes and glucose regulation in the offspring

High multivitamin intake (HV) during pregnancy increases body fat and weight and alters glucose and fatty acid metabolism in Wistar rat offspring. This study investigated the expression of peroxisome-proliferator activated receptors (PPARs) genes involved in regulation of glucose and fatty acid metabolism in their tissues. Dams received the AIN-93G diet with either the regular (RV) or 10-fold multivitamins (HV) during pregnancy. Male offspring were weaned to either the RV diet (RV-RV and HV-RV) or an obesogenic diet (RV-Ob and HV-Ob). Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction. Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning. In liver, at 14 weeks postweaning, PPAR-γ was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P=.76, postweaning diet (PD) P=.19, interaction P=.02, by two-way analysis of variance]. In muscle, PPAR-α expression was affected by GD and PD (GD P=.05, PD P<.01, interaction P=.07). In adipose tissue, PPAR-α expression was higher in all groups compared to RV-RV (GD P=.25, PD P=.85, interaction P=.03). PPAR-γ mRNA levels correlated with abdominal fat (r=0.45, P<.05) and insulin resistance index (r=0.39, P<.05). In liver, PPAR-γ expression correlated with insulin resistance index in offspring from RV (r=−0.62, P<.05), but not in those from HV dams (r=0.13, P>.05). In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue- and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring.

Expression of peroxisome proliferator activated receptor (PPAR) genes in porcine endometrium exposed in vitro to IL-6 and INFγ

The aim of the present study was to examine the effects of interferon gamma (INFγ) or interleukin 6 (IL-6) on gene expression of PPARs in the porcine endometrium on day 14 of the estrous cycle and pregnancy. Endometrial tissue (200-210 mg), after 18 h of pre-incubation, was incubated for 6 or 12 h in the presence of INFγ (5 or 50 ng/ml) or IL-6 (1 or 10 ng/ml). Gene expression was analyzed by quantitative real time RT-PCR. During the estrous cycle, neither INFγ nor IL-6 affected PPARα and PPARβ/δ transcript levels in the endometrium of the cyclic pigs incubated for 6 or 12 hours. The presence of INFγ (5 ng/ml) significantly (p<0.05) increased PPARγ1 gene expression in the tissue incubated for 12 h. During pregnancy, INFγ (50 ng/ml) significantly (p<0.05) enhanced PPARα and PPARβ/δ mRNA levels in the endometrium incubated for 6 h, whereas IL-6 (1 or 10 ng/ml) did not change their expression at any incubation time. The effect of both cytokines on PPARγ1 transcript level differed and was dependent on the incubation time. We observed an inhibitory (after 6 h of incubation, p<0.0001) and a stimulatory (after 12 h of incubation, p<0.05) effect of INFγ (5 ng/ml) or IL-6 (10 ng/ml) on PPARγ1 gene expression. The present study indicates that INFγ and IL-6 modulate PPARs gene expression in the porcine endometrium during the estrous cycle and pregnancy. The effect depends on the reproductive status of animals and the length of in vitro incubation of endometrial tissue with the treatments.

Effect of nutritional vitamin A deficiency on lipid metabolism in the rat heart: Its relation to PPAR gene expression

Objective We studied the effect of dietary vitamin A deprivation on lipid composition and mRNA expression of regulatory enzymes involved in rat heart energetic lipid metabolism and its relation to the expression of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) genes. Methods Male Wistar 21-d-old rats were fed for 3 mo with a vitamin A–free diet (vitamin A–deficient group) and the same diet plus 8 mg of retinol palmitate per kilogram of diet (control group). One group of deficient animals received the control diet 15 d before sacrifice (vitamin A–refed group). Heart ventricular and mitochondrial lipid contents were determined. Lipid synthesis was measured using radioactive precursors and acetyl-coenzyme A carboxylase and mitochondrial carnitine palmitoyltransferase-I (CPT-I) activities using radioactive substrates. Fatty acid composition of mitochondrial phospholipids was analyzed by gas–liquid chromatography. Heart expression of acetyl-coenzyme A carboxylase, CPT-I, PPAR-α, PPAR-β, RXR-α, and RXR-β was assessed by reverse transcriptase polymerase chain reaction, and CPT-I expression was also measured by real-time polymerase chain reaction. Results Vitamin A deficiency induced changes in heart ventricular lipid content and synthesis. Mitochondrial cardiolipin decreased and the proportion of phospholipids/saturated fatty acids increased. Heart activity and mRNA levels of CPT-I and expression of PPAR-α and PPAR-β genes were enhanced, whereas acetyl-coenzyme A carboxylase activity diminished. Furthermore, vitamin A deficiency decreased heart mRNA levels of RXRs. Vitamin A refeeding reverted most of the observed changes. Conclusion Lipid metabolism is significantly modified in hearts of vitamin A–deficient rats. Alteration of mitochondrial energetic processes by modifying the activity and gene expressions of the regulatory enzymes is associated with a high PPAR expression induced by vitamin A deprivation.

Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARalpha and PPARgamma is decreased. This observation suggests the possibility that PPARalpha and PPARgamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARgamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARalpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARdelta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARdelta. PPARdelta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARalpha and PPARgamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARgamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARalpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARalpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.

Increase of peroxisome proliferator-activated receptor δ gene expression in the lungs of streptozotocin-induced diabetic rats

Peroxisome proliferator-activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation while the agonists of PPAR α and PPAR γ are recently used for therapy in clinic. However, functions of PPAR δ are still unclear. In the present study, we investigated the changes of PPAR δ gene expression in the lung of diabetic rats. The mean level of mRNA transcripts encoding PPAR δ was increased in the lung isolated from streptozotocin-induced diabetic rats (STZ-diabetic rats) to about 1.6-fold of that in normal rats. Exogenous insulin at the dose sufficient to normalize the plasma glucose of STZ-diabetic rats reversed the mRNA level of PPAR δ in lungs after a 4-day treatment. Similar results were also observed in STZ-diabetic rats that received the treatment of phlorizin to reverse the plasma glucose level for 4 days. Otherwise, the protein level of PPAR δ was higher in the lung of STZ-diabetic rats than that in normal rats. Treatment with exogenous insulin or phlorizin reversed this elevated protein level of PPAR δ in the lung of STZ-diabetic rats to near the normal level. The obtained results suggest that increase of plasma glucose is responsible for the higher gene expression of PPAR δ in the lung of STZ-diabetic rats.

Differential expression of peroxisome proliferator-activated receptors alpha and gamma gene in various chicken tissues

The peroxisome proliferator-activated receptors (PPARs) are the members of superfamily of nuclear hormone receptors. A great number of studies in rodent and human have shown that PPARs were involved in the lipids metabolism. The goal of the current study was to investigate the expression pattern of PPAR genes in various tissues of chicken. The tissue samples (heart, liver, spleen, lung, kidney, stomach, intestine, brain, breast muscle and adipose) were collected from six Arber Acres broilers (8 weeks old, male and female birds are half and half). Semi-quantitative RT-PCR and Northern blot were used to characterize the expression of PPAR-α and PPAR-γ genes in the above tissues. By semi-quantitative RT-PCR, the results showed the expression level of PPAR-α gene was higher in brain, lung, kidney, heart and intestine, medium in stomach, liver and adipose than in spleen, and it did not express in breast muscle. The expression level of PPAR-γ gene was higher in adipose, medium in brain and kidney than in spleen, heart, lung, stomach and intestine, but it did not express in liver and breast muscle. Northern blot results showed that PPAR-α gene expressed in heart, liver, kidney and stomach, and the intensity of hybridization signal was the stronger in liver and kidney than in other tissues, however, PPAR-γ gene only expressed in adipose and kidney tissues. The results of this study showed the profile of PPAR gene expression in the chicken was similar to that in rodent, human and pig. However the expression profile of chicken also have its own specific trait, i.e. compared with mammals, PPAR-α gene can not be detected in skeletal muscle and PPAR-γ gene can be stronger expressed in kidney tissues. This work will provide some basic data for the PPAR genes expression and lipids metabolism of birds.

Opposite regulation of PPAR-α and -γ gene expression by both their ligands and retinoic acid in brown adipocytes

The peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors involved in the regulation of lipid metabolism and adipocyte differentiation. Little is known, however, about the control of the expression of the genes encoding each of all three receptor subtypes: α, δ, and γ. We have addressed this question in the brown adipocyte, the only cell type that co-expresses high levels of the three PPAR subtypes. Differentiation of brown adipocytes is associated with enhanced expression of PPAR genes. However, whereas PPARγ and PPARδ genes are already expressed in preadipocytes, the mRNA for PPARα appears suddenly in association with the acquisition of the terminally differentiated phenotype. Both retinoic acid isomers and PPAR agonists, specific for either PPARα or PPARγ, regulate expression of each PPAR subtype gene in the opposite way: they up-regulate PPARα and down-regulate PPARγ. The effects on PPARα mRNA are independent of protein synthesis, whereas inhibition of PPARγ mRNA expression depends on protein synthesis, except when its specific ligand prostaglandin J 2 is used. Our results indicate a strictly opposite autoregulation of PPAR subtypes, which supports specific physiological roles for them in controlling brown fat differentiation and thermogenic activity.

Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.

The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown. We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma1 and PPAR gamma2 splice variants. Both gamma1 and gamma2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma1 was detected at lower levels in liver and heart, whereas both gamma1 and gamma2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPARgamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPARgamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma2/18S in obese females vs 9.9 in lean, P = 0.003). This increase was observed in both male and females. In contrast, no differences were observed in PPAR gamma1/18S mRNA expression. There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma2/gamma1 and the body mass index of these patients. We also observed sexually dimorphic expression with increased expression of both PPAR gamma1 and PPAR gamma2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance. Nutritional regulation of PPAR gamma1 was not seen. In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture. We conclude that: (a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.

Proliferation of Myocardial Peroxisomes Caused by Several Agents and Conditions

In view of considerable gaps in our knowledge of myocardial peroxisomes, the aim of the present study is, on the basis of extensive electron-microscopic investigations, to provide reliable results on the inducibility of a proliferation (increase in the number) of these organelles in rodents' heart by several agents and conditions. As far as possible, we compared the response of heart and liver peroxisomes. Morphometric investigations were performed to assess the effectiveness of the hypolipidemic agent HL 41, erucic acid, ethanol, nifedipine, chlorpromazine, two cardiotonic drugs, isoprenaline, adriamycin, and physical exercise. The study also included spontaneously hypertensive rats (SHR). A further objective was to determine synergistic or additive effects that might occur when two or three peroxisome-proliferating stimuli act simultaneously. In every case we observed a clear peroxisome proliferation, which was found to increase by between 10 and 97% under the influence of an additional inducer. The observed increase in peroxisome number ranged from almost 200% to nearly 400%. Our results suggest that very different agents and conditions can induce myocardial peroxisome proliferation when they lead to metabolic alterations associated with an increased need for a peroxisomalβ-oxidation of fatty acids as an energy source and/or for preventing toxic effects. Regulatory mechanisms of these adaptive processes are apparently also present in the heart via peroxisome proliferator-activated receptors (PPARs) and their activation by fatty acids, which can also stimulate the PPARs gene expression. The assumption that stimulated catalase gene expression might be responsible for the induction of peroxisome proliferation as a cellular response to an extraperoxisomal oxidative stress situation (isoprenaline, adriamycin, or physical exercise) poses some critical questions. These questions pertain especially to: (a) quantitative aspects with regard to the possible effectiveness of an increase in catalase activity by two-, three-, or four-fold enhanced peroxisome numbers; (b) the role of cytoplasmic catalase; (c) the existence and importance of a myocardial mitochondrial catalase; and (d) the co-operation between the two H2O2-destroying enzymes catalase and glutathione peroxidase.

Expression of the peroxisome proliferator-activated receptor gene is decreased in experimental alcoholic liver disease

Peroxisome proliferator-activated receptor (PPAR) and retinoid x receptor (RXR) play important roles in fatty acid metabolism. The present study examined the regulation of retinoic acid receptor (RARα, β, and γ), RXR (α, β, and γ), PPAR, cytochrome P450 2E1 (CYP2E1), catalase, and β-actin gene expression in chronic alcoholic liver disease in the rat. The results demonstrated that the expression of genes for RAR and RXR isoforms and catalase were not altered by ethanol in the fatty liver. In contrast, the levels of PPAR and CYP2E1 mRNAs were down- and up-regulated by ethanol in the liver, respectively. The levels of CYP2E1 mRNAs correlated positively with blood alcohol levels (BAL). In addition, ethanol induced expression of β-actin mRNA was also proportional to the BAL. The level of PPAR mRNA and the content of polyunsaturated fatty acid decreased in ethanol-fed rat livers. Decreased PPAR gene expression in ethanol-fed rats might result from a decrease in the content of polyunsaturated fatty acid in the liver. However, the activities of enzymes involved in hepatic lipid metabolism, including acyl CoA synthetase, acyl CoA oxidase, catalase, and protein kinase C, were not changed by ethanol treatment. The significance of down-regulation of PPAR gene in alcoholic liver disease is discussed.