Search results for "Peroxisome Proliferators"
showing 9 items of 9 documents
The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Defic…
2007
Abstract Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csbm/m/Ogg1−/− mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csbm/m/Ogg1−/− mice and repair-proficient controls with the peroxisome proliferator WY-14…
Effects of peroxisome proliferator-activated receptor alpha activation on pathways contributing to cholesterol homeostasis in rat hepatocytes
2004
International audience; Peroxisome proliferator-activated receptor alpha (PPARa) activation by fibrates controls expression of several genes involved in hepatic cholesterol metabolism. Other genes could be indirectly controlled in response to changes in cellular cholesterol availability. To further understand how fibrates may affect cholesterol synthesis, we investigated in parallel the changes in the metabolic pathways contributing to cholesterol homeostasis in liver. Ciprofibrate increased HMG-CoA reductase and FPP synthase mRNA levels in rat hepatocytes, together with cholesterogenesis from [14C] acetate and [3H] mevalonate. The up-regulation observed in fenofibrate- and WY-14,643-treate…
A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα-mediated upregulation of SREBP-2 target genes in the liver.: ThB …
2011
International audience; Peroxisomal 3-ketoacyl-CoA thiolase B (Thb) catalyzes the final step in the peroxisomal β-oxidation of straight-chain acyl-CoAs and is under the transcription control of the nuclear hormone receptor PPARα. PPARα binds to and is activated by the synthetic compound Wy14,643 (Wy). Here, we show that the magnitude of Wy-mediated induction of peroxisomal β-oxidation of radiolabeled (1-(14)C) palmitate was significantly reduced in mice deficient for Thb. In contrast, mitochondrial β-oxidation was unaltered in Thb(-/-) mice. Given that Wy-treatment induced Acox1 and MFP-1/-2 activity at a similar level in both genotypes, we concluded that the thiolase step alone was respons…
Phosphorylation of peroxisome proliferator-activated receptor α in rat Fao cells and stimulation by ciprofibrate
1999
The basic mechanism(s) by which peroxisome proliferators activate peroxisome proliferator-activated receptors (PPARs) is (are) not yet fully understood. Given the diversity of peroxisome proliferators, several hypotheses of activation have been proposed. Among them is the notion that peroxisome proliferators could activate PPARs by changing their phosphorylation status. In fact, it is well known that several members of the nuclear hormone receptor superfamily are regulated by phosphorylation. In this report, we show that the rat Fao hepatic-derived cell line, known to respond to peroxisome proliferators, exhibited a high content of PPARalpha. Alkaline phosphatase treatment of Fao cell lysat…
Functional characterization of a peroxisome proliferator response-element located in the intron 3 of rat peroxisomal thiolase B gene.
2003
Expression of the rat peroxisomal 3-ketoacyl-CoA thiolase gene B is induced by peroxisome proliferators. Although a sequence element like a peroxisome proliferator-activated receptor (PPAR)-binding site is located in the promoter region of this gene, we previously found that this element is competent for the activation by hepatocyte nuclear factor-4, but not functional with PPARalpha. We describe here a new peroxisome proliferator-response element located in the intron 3 (+1422/+1434) that binds in vitro the PPARalpha/retinoid X receptor alpha heterodimer and confers the induction by PPARalpha in transfection assays. We propose a model of regulation of the rat thiolase B gene involving thos…
The peroxisome proliferator response element (PPRE) present at positions -681/-669 in the rat liver 3-ketoacyl-CoA thiolase B gene functionally inter…
2000
Although previous data showed that the putative thiolase B PPRE located at -681/-669 bind the PPARalpha-RXRalpha heterodimer in vitro (Kliewer et al. (1992) Nature 358, 771-774), there is no evidence about the functional role of this element. By gel mobility-shift assay, we found an interaction of this PPRE with not only PPARalpha but also with HNF-4. By transfection of cells with the putative PPRE-driven luciferase reporter vector and PPARalpha, we found no significant activation of the luciferase gene expression, in contrast to the case with reporter expression driven by the PPRE of the peroxisomal bifunctional enzyme. On the other hand, HNF-4 activated the luciferase gene expression driv…
Ciprofibrate stimulates protein kinase C-dependent phosphorylation of an 85 kDa protein in rat Fao hepatic derived cells
2000
The effect of ciprofibrate on early events of signal transduction was previously studied in Fao cells. Protein kinase C (PKC) assays performed on permeabilized cells showed a more than two-fold increase in PKC activity in cells treated for 24 h with 500 microM ciprofibrate. To show the subsequent effect of this increase on protein phosphorylation, the in vitro phosphorylation on particulate fractions obtained from Fao cells was studied. Among several modifications, the phosphorylation of protein(s) with an apparent molecular mass of 85 kDa was investigated. This modification appeared in the first 24 h of treatment with 500 microM ciprofibrate. It was shown to occur on Ser/Thr residue(s). It…
Regulation of the peroxisomal β-oxidation-dependent pathway by peroxisome proliferator-activated receptor α and kinases
2000
The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, severa…
Carcinogenic aspect of xenobiotic molecules belonging to the peroxisome proliferator family.
1999
It is known that a short-term exposure of rat, mice or incubation of hepatic cells with fibrate molecules leads to increase in peroxisome number and cell hyperplasia. Further, long-term incubation of cells (at least a year) show transformed characteristics with foci and nodules. To explain the hepatocarcinogenic effect of peroxisome proliferators in rodents we studied the effect of peroxisome proliferators on rat liver oncogenes expression. Earlier, we reported an increase in liver and kidney mRNA level of c-myc and N-myc. Since several metabolic genes are activated by PPAR (peroxisome proliferators activated receptor) through a PPRE (peroxisome proliferator response element), we suggest th…