15-Deoxy-Δ12,14-prostaglandin J2 and peroxisome proliferator-activated receptor γ (PPARγ) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPARγ agonist on nitridergic and lipid placental metabolism

2005 ◽  
Vol 17 (4) ◽  
pp. 423 ◽  
Author(s):  
E. Capobianco ◽  
A. Jawerbaum ◽  
M. C. Romanini ◽  
V. White ◽  
C. Pustovrh ◽  
...  
Keyword(s):  
De Novo ◽  
Lipid Synthesis ◽  
Diabetic Rats ◽  
Lipid Homeostasis ◽  
Diabetic Rat ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Prostaglandin J2

15-Deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) is a peroxisome proliferator-activated receptor γ (PPARγ) ligand that regulates lipid homeostasis and has anti-inflammatory properties in many cell types. We postulated that 15dPGJ2 may regulate lipid homeostasis and nitric oxide (NO) levels in term placental tissues and that alterations in these pathways may be involved in diabetes-induced placental derangements. In the present study, we observed that, in term placental tissues from streptozotocin-induced diabetic rats, 15dPGJ2 concentrations were decreased (83%) and immunostaining for nitrotyrosine, indicating peroxynitrite-induced damage, was increased. In the presence of 15dPGJ2, concentrations of nitrates/nitrites (an index of NO production) were diminished (40%) in both control and diabetic rats, an effect that seems to be both dependent on and independent of PPARγ activation. Exogenous 15dPGJ2 did not modify lipid mass, but decreased the incorporation of 14C-acetate into triacylglycerol (35%), cholesteryl ester (55%) and phospholipid (32%) in placenta from control rats, an effect that appears to be dependent on PPARγ activation. In contrast, the addition of 15dPGJ2 did not alter de novo lipid synthesis in diabetic rat placenta, which showed decreased levels of PPARγ. We conclude that 15dPGJ2 modulates placental lipid metabolism and NO production. The concentration and function of 15dPGJ2 and concentrations of PPARγ were altered in placentas from diabetic rats, anomalies probably involved in diabetes-induced placental dysfunction.

Modulatory effect of leptin on nitric oxide production and lipid metabolism in term placental tissues from control and streptozotocin-induced diabetic rats

2004 ◽  
Vol 16 (3) ◽  
pp. 363 ◽  
Author(s):  
Verónica White ◽  
Elida González ◽  
Evangelina Capobianco ◽  
Carolina Pustovrh ◽  
Carlos Soñez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
De Novo ◽  
Lipid Synthesis ◽  
Placental Tissue ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Diabetic Rat ◽  
No Production

Leptin production by placental tissues contributes to its circulating levels and functions. The diabetic pathology induces alterations in leptin levels. In the present study, leptin levels were evaluated in placental tissue from control and neonatal streptozotocin-induced (n-STZ) diabetic rats during late gestation. The effects of leptin levels on the generation of nitric oxide (NO), prostaglandin (PG) E2 production and lipid metabolism were examined. Leptin levels were diminished in placentas from n-STZ diabetic rats compared with controls (P < 0.01). These differences were also evident when leptin was evaluated immunohistochemically. Addition of leptin (1 nm) in vitro enhanced NO production in control (66%) and diabetic placentas (134%) by stimulating NO synthase activity (by 38% and 54%, respectively). The addition of leptin increased PGE2 production in placentas from control (173%) and diabetic rats (83%) and produced a 50% decrease in placental lipid levels (phospholipids, triacylglycerides, cholesterol and cholesteryl ester) without involving a reduction in de novo lipid synthesis. These data indicate that leptin enhances the production of placental NO and PGE2, vasoactive agents that modify placental blood flow, and that leptin stimulates placental lipid metabolism, probably generating more lipids for transfer to the fetus. In the diabetic rat, placental leptin was reduced, probably as a response to the maternal environment to locally regulate the transfer of nutrients to the developing fetus.

scholarly journals PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats

2011 ◽  
Vol 47 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Nora Martínez ◽  
Melisa Kurtz ◽  
Evangelina Capobianco ◽  
Romina Higa ◽  
Verónica White ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
Lipid Synthesis ◽  
Diabetic Rats ◽  
Placental Weight ◽  
Peroxidation Of Lipids ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Regulate Lipid Metabolism

Maternal diabetes impairs fetoplacental metabolism and growth. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor capable of regulating lipid metabolism and inflammatory pathways. In this study, we analyzed whether placental and fetal PPARα activation regulates lipid metabolism and nitric oxide (NO) production in term placentas from diabetic rats. Diabetes was induced by neonatal streptozotocin administration. On day 21 of pregnancy, placentas from control and diabetic rats were cultured in the presence of PPARα agonists (clofibrate and leukotriene B4 (LTB4)) for further evaluation of levels, synthesis, and peroxidation of lipids as well as NO production. Besides, on days 19, 20, and 21 of gestation, fetuses were injected with LTB4, and the placentas were explanted on day 21 of gestation for evaluation of placental weight and concentrations of placental lipids, lipoperoxides, and NO metabolites. We found that placentas from diabetic rats showed reduced PPARα concentrations. They presented no lipid overaccumulation but reduced lipid synthesis, parameters negatively regulated by PPARα activators. Lipid peroxidation and NO production, increased in placentas from diabetic rats, were negatively regulated by PPARα activators. Fetal PPARα activation in diabetic rats does not change placental lipid concentrations but reduced placental weight and NO production. In conclusion, PPARα activators regulate lipid metabolism and NO production in term placentas from diabetic rats, an activation that regulates placental growth and can partly be exerted by the developing fetus.

scholarly journals Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8054 ◽  
Author(s):  
Vanessa Cheng ◽  
Subham Dasgupta ◽  
Aalekhya Reddam ◽  
David C. Volz
Keyword(s):  
Embryonic Development ◽  
Cell Fate ◽  
De Novo ◽  
Early Embryonic Development ◽  
Zebrafish Embryos ◽  
Peroxisome Proliferator ◽  
Dorsoventral Patterning ◽  
Peroxisome Proliferator Activated Receptor ◽  
Critical Window ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone—a potent human PPARγ agonist—exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.

scholarly journals De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination

2018 ◽  
Vol 217 (4) ◽  
pp. 1353-1368 ◽  
Author(s):  
Laura Montani ◽  
Jorge A. Pereira ◽  
Camilla Norrmén ◽  
Hartmut B.F. Pohl ◽  
Elisa Tinelli ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Ex Vivo ◽  
Intrinsic Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endogenous Fatty Acid ◽  
Pparγ Agonist

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ–regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.

scholarly journals Lipid Acyl Chain Remodeling in Yeast

2015 ◽  
Vol 8s1 ◽  
pp. LPI.S31780 ◽  
Author(s):  
Mike F. Renne ◽  
Xue Bao ◽  
Cedric H. De Smet ◽  
Anton I. P. M. De Kroon
Keyword(s):  
Intracellular Transport ◽  
De Novo ◽  
Acyl Chain ◽  
Model Organism ◽  
Lipid Synthesis ◽  
Membrane Lipid ◽  
Lipid Homeostasis ◽  
Synthetic Process ◽  
Acyl Chains ◽  
Phospholipid Acyl Chain

Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed.

scholarly journals Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro

2002 ◽  
Vol 87 (3) ◽  
pp. 1129-1133 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
George Zhang ◽  
James C. Garmey
Keyword(s):  
Gene Expression ◽  
Polycystic Ovarian Syndrome ◽  
De Novo ◽  
Drug Concentrations ◽  
Thecal Cells ◽  
Cyp17 Gene ◽  
Pparγ Agonist ◽  
Ovarian Syndrome ◽  
Prostaglandin J2

Polycystic ovarian syndrome (anovulatory hyperandrogenism) is marked by adolescent onset of systemic hyperinsulinism, oligoovulation, hirsutism, excessive LH and androgen secretion, and variable reduction in fertility. Insulin and LH are believed to act in concert to promote ovarian androgen hypersecretion in this disorder. Administration of troglitazone, an insulin-sensitizing agent and putative PPARγ agonist, can decrease hyperinsulinism, suppress T production, and ameliorate oligoovulation in some women with this endocrinopathy. The present study tests the hypothesis that troglitazone directly inhibits de novo androgen biosynthesis stimulated jointly by LH and insulin in primary cultures of (porcine) thecal cells. We show that troglitazone dose-dependently antagonizes LH/insulin’s combined stimulation of androstenedione and T production by thecal cells in vitro. Consistent steroidogenic inhibition of 80–95% was achieved at drug concentrations of 3–6.8 μm (P &lt; 0.001). Exposure of thecal cells to the thiazolidinedione derivative also blocked bihormonally stimulated accumulation of CYP17 (cytochrome P450 17 α-hydroxylase/C17–20 lyase) gene expression, as reflected by decreased accumulation of cognate heterogeneous nuclear RNA and mRNA (by 30–65%; P &lt; 0.05). Moreover, troglitazone suppressed LH/insulin-induced phosphorylation of the 52-kDa immunoprecipitated CYP17 enzyme by 88% (P &lt; 0.001). A putative natural agonist of PPARγ nuclear transcription, 15-deoxy-δ-12,14-prostaglandin J2, also inhibited LH/insulin-driven androstenedione biosynthesis and CYP17 gene expression in thecal cells. In conclusion, a synthetic thiazolidinedione (troglitazone) and a natural ligand of PPARγ (15-deoxy-δ-12,14-prostaglandin J2) effectively impede the concerted stimulation by LH and insulin of in vitro thecal cell androgen production, CYP17 gene expression, and CYP17 protein phosphorylation. This ensemble of inhibitory actions on LH/insulin-stimulated steroidogenesis offers a plausible mechanistic basis for at least part of the observed clinical efficacy of troglitazone in mitigating androgen excess in women with polycystic ovarian syndrome.

scholarly journals Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

2012 ◽  
Vol 287 (42) ◽  
pp. 35161-35169 ◽  
Author(s):  
Jundong Zhou ◽  
Shuyu Zhang ◽  
Jing Xue ◽  
Jori Avery ◽  
Jinchang Wu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Hypoxia Inducible Factor ◽  
Proteasome Inhibitors ◽  
Tube Formation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypoxia Inducible Factor 1Α ◽  
Anticancer Properties ◽  
Pparγ Agonist ◽  
Expression And Activity

Activation of peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARα activation on the hypoxia-inducible factor-1α (HIF-1α) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1α expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity, and addition of a PPARα antagonist attenuated the suppression of HIF-1α signaling. Activation of PPARα attenuated hypoxia-induced HA-tagged HIF-1α protein expression without affecting the HA-tagged HIF-1α mutant protein level, indicating that PPARα activation promotes HIF-1α degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARα-mediated suppression of HIF-1α expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of HIF-1α to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Following PPARα-mediated suppression of HIF-1α signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARα suppresses hypoxia-induced HIF-1α signaling in cancer cells, providing novel insight into the anticancer properties of PPARα agonists.

scholarly journals Suppression of Peroxisome Proliferator-Activated Receptor γ-Coactivator-1α Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4074-4083 ◽  
Author(s):  
Ji-Won Kim ◽  
Young-Hye You ◽  
Dong-Sik Ham ◽  
Jae-Hyoung Cho ◽  
Seung-Hyun Ko ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Receptor Site ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Dysfunction

Abstract Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1α in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1α in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1α in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1α also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1α small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1α but were rescued by Ad-siPGC-1α. PGC-1α binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1α. Ad-siPGC-1α injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1α expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1α, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.

Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency

2000 ◽  
Vol 349 (1) ◽  
pp. 353-356 ◽  
Author(s):  
Cynthia J. MEININGER ◽  
Rebecca S. MARINOS ◽  
Kazuyuki HATAKEYAMA ◽  
Raul MARTINEZ-ZAGUILAN ◽  
Jose D. ROJAS ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Diabetic Rats ◽  
Bb Rat ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Bb Rats ◽  
Metabolic Basis ◽  
Rate Limiting

Endothelial cells (EC) from diabetic BioBreeding (BB) rats have an impaired ability to produce NO. This deficiency is not due to a defect in the constitutive isoform of NO synthase in EC (ecNOS) or alterations in intracellular calcium, calmodulin, NADPH or arginine levels. Instead, ecNOS cannot produce sufficient NO because of a deficiency in tetrahydrobiopterin (BH4), a cofactor necessary for enzyme activity. EC from diabetic rats exhibited only 12% of the BH4 levels found in EC from normal animals or diabetes-prone animals which did not develop disease. As a result, NO synthesis by EC of diabetic rats was only 18% of that for normal animals. Increasing BH4 levels with sepiapterin increased NO production, suggesting that BH4 deficiency is a metabolic basis for impaired endothelial NO synthesis in diabetic BB rats. This deficiency is due to decreased activity of GTP-cyclohydrolase I, the first and rate-limiting enzyme in the de novo biosynthesis of BH4. GTP-cyclohydrolase activity was low because of a decreased expression of the protein in the diabetic cells.

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