scholarly journals Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia

1998 ◽  
Vol 332 (3) ◽  
pp. 689-693 ◽  
Author(s):  
Alex R. BELL ◽  
Richard SAVORY ◽  
Neill J. HORLEY ◽  
Agharul I. CHOUDHURY ◽  
Maurice DICKINS ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Molecular Basis ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Luciferase Reporter Gene ◽  
Pig Liver ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Response Element ◽  
Guinea Pig Liver

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor α (PPARα) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARα. The guinea-pig PPARα showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P≈ 0.06). The guinea-pig PPARα cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARα RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARα mediated any physiological effects, guinea pigs were exposed to two selective PPARα agonists, Wy-14,643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.

scholarly journals Cyclin G2 Regulates Adipogenesis through PPARγ Coactivation

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5247-5254 ◽  
Author(s):  
Victor Aguilar ◽  
Jean-Sébastien Annicotte ◽  
Xavier Escote ◽  
Joan Vendrell ◽  
Dominique Langin ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cell Cycle Regulators ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclin G2 ◽  
Regulatory Effects

Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.

Tumor necrosis factor-α inhibits peroxisome proliferator-activated receptor γ activity at a posttranslational level in hepatic stellate cells

2004 ◽  
Vol 286 (5) ◽  
pp. G722-G729 ◽  
Author(s):  
Chin K. Sung ◽  
Hongyun She ◽  
Shigang Xiong ◽  
Hidekazu Tsukamoto
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Critical Event ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

Diminished activity of peroxisome proliferator-activated receptor γ (PPARγ) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARγ regulation by TNF-α in an HSC line designated as BSC. In BSC, TNF-α decreased both basal and ligand (GW1929)-induced PPARγ mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-α showed decreased binding of PPARγ to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARγ1 expression vector and a PPRE-luciferase reporter gene, TNF-α decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-α increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser82 of PPARγ1 and resultant negative regulation of PPARγ transactivity. In fact, TNF-α failed to inhibit transactivity of a Ser82Ala PPARγ1 mutant in BSC. TNF-α-mediated inhibition of PPARγ transactivity was not blocked with a Ser32Ala/Ser36Ala mutant of inhibitory NF-κBα (IκBα). These results suggest that TNF-α inhibits PPARγ transactivity in cultured HSC, at least in part, by diminished PPARγ-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser82 of PPARγ1, but not via the NF-κB pathway.

scholarly journals Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression

2020 ◽  
Vol 10 (1) ◽  
pp. 126
Author(s):  
Jennifer M. Enright ◽  
Sheng Zhang ◽  
Christina Thebeau ◽  
Emily Siebert ◽  
Alexander Jin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Elevated Serum ◽  
Oscillatory Potentials ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Serum Triglycerides ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Peroxisome Proliferator Response Element

Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.

scholarly journals Peroxisome Proliferator-Activated Receptor-γ Increases Adiponectin Secretion via Transcriptional Repression of Endoplasmic Reticulum Chaperone Protein ERp44

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3195-3203 ◽  
Author(s):  
Qinqiang Long ◽  
Ting Lei ◽  
Bin Feng ◽  
Changjun Yin ◽  
Dan Jin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Repression ◽  
Energy Homeostasis ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Peroxisome Proliferator Response Element

Adiponectin, an adipocyte-derived hormone, is a versatile player involved in the regulation of energy homeostasis, cardiovascular disease, and diabetes. Within adipocytes, adiponectin is retained in the lumen of the endoplasmic reticulum (ER) by binding to the thiol protein ER resident protein 44 kDa (ERp44), which is apparently regulated by the activation of nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ. However, the precise role of ERp44 in adiponectin secretion remains elusive. In the present study, we investigated the functional correlation between ERp44 and adiponectin in a pig model. The transcription of porcine ERp44 was regulated by PPARγ, which was consistent with the finding of putative peroxisome proliferator response element sites within ERp44 promoter. Using chromatin immunoprecipitation and luciferase reporter assays, we demonstrated that the transcription of porcine ERp44 is repressed through binding of PPARγ to a peroxisome proliferator response element site located between positions −981 and −1004 in its 5′-flanking region. In human embryonic kidney 293 cells stably transfected with cDNA encoding porcine adiponectin, the secretion of adiponectin was significantly up-regulated and the ERp44 mRNA was down-regulated observably, by either the treatment of PPARγ agonist rosiglitazone or the overexpression of PPARγ in these cells. Taken together, our results indicated that PPARγ is an essential regulatory factor for the transcriptional activity of ERp44, which in turn controls the secretion of adiponectin.

scholarly journals Potentiation of TNF-α–Stimulated Group IIA Phospholipase A2 Expression by Peroxisome Proliferator–Activated Receptor α Activators in Rat Mesangial Cells

2002 ◽  
Vol 13 (3) ◽  
pp. 611-620 ◽  
Author(s):  
Kirsten Scholz-Pedretti ◽  
Annette Gans ◽  
Karl-Friedrich Beck ◽  
Josef Pfeilschifter ◽  
Marietta Kaszkin
Keyword(s):  
Promoter Activity ◽  
Mesangial Cells ◽  
Site Directed Mutagenesis ◽  
Lipid Lowering ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Glomerular Mesangial Cells ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

ABSTRACT. Natural activators of peroxisome proliferator–activated receptors (PPAR) are lipid metabolites, including those produced by phospholipases A2 (PLA2). In glomerular mesangial cells, the secreted group IIA PLA2 (sPLA2-IIA), which is thought to be a crucial factor in pathologic processes in the kidney, may provide free fatty acids and eicosanoids directly or indirectly, by activating a cytosolic PLA2. The scope of this study was to investigate whether synthetic PPARα activators have an effect on sPLA2-IIA mRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA2-IIA transcription. In the presence of tumor necrosis factor–α (TNF-α), the PPARα agonists WY14643 and LY171883 as well as the lipid-lowering compound clofibrate potentiated expression, secretion, and activity of group IIA sPLA2 in mesangial cells. MK886, known as a noncompetitive inhibitor of PPARα, completely abolished the potentiation of sPLA2-IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPARα. When cells were transfected with different constructs of the rat sPLA2-IIA promoter fused to a luciferase reporter gene, a stimulation with TNF-α in the presence of the PPARα activators caused an enhanced promoter activity compared with that induced by TNF-α alone. Site-directed mutagenesis of a putative PPRE site in the sPLA2-IIA promoter abolished the potentiating effect of PPARα agonists, thus strongly indicating its contribution to the enhanced promoter activity. In summary, this study shows that the rat sPLA2-IIA promoter is sensitive to PPARα agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA2-IIA in rat mesangial cells.

scholarly journals Differential regulation by a peroxisome proliferator of the different multifunctional proteins in guinea pig: cDNA cloning of the guinea pig D-specific multifunctional protein 2

1998 ◽  
Vol 330 (3) ◽  
pp. 1361-1368 ◽  
Author(s):  
Françoise CAIRA ◽  
Marie-Claude CLÉMENCET ◽  
Mustapha CHERKAOUI-MALKI ◽  
Martine DIEUAIDE-NOUBHANI ◽  
Corinne PACOT ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Acid Synthesis ◽  
Northern Blotting ◽  
Peroxisome Proliferator ◽  
Pig Liver ◽  
Multifunctional Protein ◽  
Mrna Species ◽  
Hepatic Expression ◽  
Guinea Pig Liver

After our previous report on the cloning of two cDNA species in guinea pig, both encoding the same hepatic 79 kDa multifunctional protein 1 (MFP-1) [Caira, Cherkaoui-Malki, Hoefler and Latruffe (1996) FEBS Lett. 378, 57-60], here we report the cloning of a cDNA encoding a second multifunctional peroxisomal protein (MFP-2) in guinea-pig liver. This 2356 nt cDNA encodes a protein of 735 residues (79.7 kDa) whose sequence shows 83% identity with rat MFP-2 [Dieuaide-Noubhani, Novikov, Baumgart, Vanhooren, Fransen, Goethals, Vandekerckhove, Van Veldhoven and Mannaerts (1996) Eur. J. Biochem. 240, 660-666]. In parallel, we studied the effect of ciprofibrate, a hypolipaemic agent also known as peroxisome proliferator in rodent, on the expression of MFP-1 and MFP-2 (2.6 kb) in rats and guinea pigs. By Northern blotting analysis we demonstrated that three MFP-1-related mRNA species are expressed in the guinea-pig liver. The expression of two of them (3.5 and 2.6 kb) is slightly increased by ciprofibrate, whereas the 3.0 kb MFP-1 mRNA is, unlike the rat one, strongly down-regulated in guinea pigs treated with ciprofibrate. In a similar way, the hepatic expression of the guinea-pig 2.6 kb MFP-2 mRNA is also down-regulated in guinea pigs treated with ciprofibrate. These results demonstrate (1) that in contrast with the unique 3.0 kb MFP-1 rat mRNA, at least three hepatic MFP-1-related mRNA species are co-expressed in guinea pig; and (2) that, opposed to the accepted idea of non-responsiveness of the guinea pig to ciprofibrate, this drug affects MFP-1 and MFP-2 gene expression in this species. Also, the mRNA species for acyl-CoA oxidase and thiolase, two other enzymes of the peroxisomal β-oxidation pathway that are induced severalfold in responsive species are down-regulated in guinea pig. This paper is the first, to our knowledge, reporting the down-regulation of the expression of genes encoding enzymes involved in the peroxisomal β-oxidation of fatty acids (MFP-1) and bile acid synthesis (MFP-2) in mammals.

The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs

1993 ◽  
Vol 11 (1) ◽  
pp. 37-47 ◽  
Author(s):  
I Issemann ◽  
R A Prince ◽  
J D Tugwood ◽  
S Green
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Physiological Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisomal Enzyme ◽  
Oxidase Gene ◽  
Acyl Coa Oxidase ◽  
Peroxisome Proliferator Response Element

ABSTRACT The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.

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