Central Role of Peroxisome Proliferator–Activated Receptors in the Actions of Peroxisome Proliferators

Corton, J. Christopher; Anderson, Steven P.; Stauber, Anja J.

doi:10.1146/annurev.pharmtox.40.1.491

Cited by 314 publications

(261 citation statements)

References 126 publications

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“…Its primary biochemical responses are mediated through activation of the peroxisome proliferator receptor alpha (PPARalpha), and there is good evidence to suggest that the tumor promotional effects of this and other peroxisome proliferators are also mediated through this receptor (for a recent review, see ref 13). We observed a decrease in the formation of GSTP-positive foci dependent on CF-dose in the present study.…”

Section: Discussionsupporting

confidence: 62%

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

et al. 2003

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A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.

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Section: Discussionsupporting

confidence: 62%

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

et al. 2003

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“…As positive controls for the Wytreated animals, we examined the expression of 2 genes commonly used as markers for peroxisome proliferator exposure. 1 Prior to PH or Wy treatment, Ppar␣-null mice showed greatly reduced (Aco, 50% reduction) or no expression (Cyp4a14) of these genes (Fig. 5).…”

Section: Expression Of Genes Involved In Progressionmentioning

confidence: 97%

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

et al. 2002

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Peroxisome proliferator chemicals, acting via the peroxisome proliferator-activated receptor-␣ (Ppar␣), are potent hepatic mitogens and carcinogens in mice and rats. To test whether Ppar␣ is required for hepatic growth in response to other stimuli, we studied liver regeneration and hepatic gene expression following partial hepatectomy (PH) of wild-type and Ppar␣-null mice. Ppar␣-null mice had a 12-to 24-hour delay in liver regeneration associated with a delayed onset and lower peak magnitude of hepatocellular DNA synthesis. Furthermore, these mice had a 24-hour lag in the hepatic expression of the G 1 /S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1␤ cytokine gene. Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Ppar␣-null mice, after acute exposure to the potent Ppar␣ agonist Wy-14,643, indicating a role for Ppar␣ in regulating the expression of these genes. Expression of the fatty acid -hydroxylase gene Cyp4a14, a commonly used indicator gene for Ppar␣ activation, was strongly induced in wild-type mice after hepatectomy, suggesting that altered hepatocyte lipid processing may also contribute to the impaired regeneration in mice lacking the Ppar␣ gene. In conclusion, liver regeneration in Ppar␣-null mice is transiently impaired and is associated with altered expression of genes involved in cell cycle control, cytokine signaling, and fat metabolism. (HEPATOLOGY 2002;36:544-554.) P eroxisome proliferator (PP) xenobiotics are potent hepatic mitogens and carcinogens in mice and rats. 1 Increases in hepatocyte replication and tumor formation after PP exposure require activation of the peroxisome proliferator-activated receptor-␣ (Ppar␣). 2 Many transcriptional targets of Ppar␣ have been identified, but none have direct roles in regulating cell proliferation or apoptosis. One of the most effective models for studying hepatocellular proliferation is liver regeneration following hepatocellular loss because of partial hepatectomy (PH) or chemical damage. 3 In the original technique for PH described by Higgins and Anderson in 1931, 4 resection of 70% of the hepatic mass of a rat results in 95% of the remaining hepatocytes rapidly entering the cell cycle. DNA synthesis follows about 12 to 14 hours after resection and reaches a maximum activation at 24 hours. These events occur about 20 hours later in mice. The original mass of the liver is restored within 7 days, with most of the recovery occurring by 3 days. 4 The signals that stimulate and maintain this process are not entirely clear but include the transcriptional activation of several groups of genes in a distinct temporal order. 3,[5][6][7] First, hepatocytes must be primed, presumably by cytokines, to respond to various growth factors. After priming, transition from G 0 to G 1 phases of the cell cycle requires induction of immediate-early class genes, which begins at about 30 minutes post-PH and lasts for about 4 hours. Progression of hepatocytes in vivo through late G 1 phase requires gr...

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“…PPAR-mediated transactivation of target genes involves their dimerization with the retinoid X receptor (RXR) following ligand activation and binding of the resulting heterodimer to specific PPAR response elements (PPREs) located within the promoters/enhancers of target genes (10). PPAR␥ also utilize different coactivators to specify selective target gene transcription, which include p300 (or CBP) (11,12), the SRC-1 class of coactivators (13,14), PGC-1 and PGC-2 (15,16), ARA70 (17), and DRIP205 (or TRAP220) (18,19).…”

mentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway

Sharma

Pradeep

Wong

et al. 2004

Journal of Biological Chemistry

123

111

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The transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPAR␥1 and PPAR␥2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPAR␥2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of ␤-catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. ␤-Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with Ecadherin and other cellular processes via regulating target gene transcription in association with TCF/LEF transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, one involving glycogen synthase kinase 3␤ (GSK3␤) and the other involving p53-Siah-1, degrade excess ␤-catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound ␤-catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPAR␥2 activation inhibited GSK3␤ kinase activity, and pharmacological inhibition of GSK3␤ activity was unable to restore ␤-catenin expression following PPAR␥2 activation. Additionally, this ␤-catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPAR␥2-mediated degradation of ␤-catenin, and incubation with TZD increased ubiquitination of ␤-catenin. We conclude that PPAR␥2-mediated suppression of ␤-catenin levels involves a novel APC/ GSK3␤/p53-independent ubiquitination-mediated proteasomal degradation pathway.

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Central Role of Peroxisome Proliferator–Activated Receptors in the Actions of Peroxisome Proliferators

Cited by 314 publications

References 126 publications

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway

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