Impaired skin wound healing in peroxisome proliferator–activated receptor (PPAR)<b>α</b> and PPAR<b>β</b> mutant mice

Michalik, Liliane; Desvergne, Béatrice; Tan, Nguan Soon; Basu-Modak, Sharmila; Escher, Pascal; Rieusset, Jennifer; Peters, Jeffrey M.; Kaya, Gürkan; Gonzalez, Frank J.; Zákány, József; Metzger, Daniel; Chambon, Pierre; Duboule, Denis; Wahli, Walter

doi:10.1083/jcb.200011148

Cited by 383 publications

(450 citation statements)

References 52 publications

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“…Peroxisome proliferatoractivated receptord may mediate the antiapoptotic effect through activation by prostacyclin (PGI(2)), a major prostaglandin with antiapoptotic activity (Gupta et al, 2000;Cutler et al, 2003). There is also cumulative evidence regarding the antiapoptotic effects of PPARd in keratinocyte and colon cancer cells (Michalik et al, 2001;Di-Poi et al, 2002;Shureiqi et al, 2003;Gupta et al, 2004). These findings suggest that PPARd may play a certain tumour-promoting role in intestinal tumours or CRC cells by modulating cell survival and apoptosis, which is in line with our observation that PPARd was exclusively expressed in those CRC cells that also exhibited highly malignant morphology.…”

Section: Discussionsupporting

confidence: 88%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

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Whether peroxisome proliferator-activated receptor (PPAR) d is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARd expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARd in CRC. Immunohistochemical analysis indicated that PPARd expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARd protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARd-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARd-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARd in CRC samples. Based on Western blot analysis and quantitative RT -PCR, high PPARd protein expression correlated with high PPARd mRNA levels. Peroxisome proliferator-activated receptor d may have a supporting role in tumorigenesis, and the close association between PPARd expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.

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Section: Discussionsupporting

confidence: 88%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

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“…Purebred wild-type and PPARβ-null mice on a SV/129 background were used and have been previously described [22,23]. Primary hepatocytes were isolated from two male wildtype mice (10 day old) and two male PPARβ-null mice (5 day old).…”

Section: Isolation Maintenance and Infection Of Primary Hepatocytesmentioning

confidence: 99%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

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103

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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“…[8][9][10] Its role in cellular response to inflammation is also well characterized. 11,12 As for PPARa and PPARg, fatty acids are natural ligands of PPARdelta. 13 A polymorphism in the 5 0 untranslated region of the PPAR-delta gene has been identified, the À87T4C polymorphism (also named þ 294T4C), 14,15 and shown to be associated with the plasma lipid profile.…”

Section: Introductionmentioning

confidence: 99%

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

et al. 2006

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The metabolic syndrome (MS) is influenced by genetic and environmental factors. Peroxisome proliferator-activated receptor delta (PPAR-delta), a transcription factor involved in lipid metabolism, is a candidate gene for the MS. Objective: We verified whether genetic variants in this gene are associated with the MS and whether dietary fatty acids interact with the À87T4C polymorphism. Methods: By direct sequencing, we identified 15 variants in the PPAR-delta gene and analyses were pursued with the À87T4C polymorphism for 340 subjects. Results: Metabolic variables were comparable among each genotype group. The À87T4C polymorphism, fat intake and the interaction accounted, respectively for 2.2, 1.9 and 1.5% of the variance in high-density lipoprotein cholesterol (HDL-C) levels (Po0.05) (age, sex and energy intake were included into the model). The total cholesterol/HDL-C ratio was also modulated by a gene-diet interaction and by the -87T4C polymorphism (Po0.05). No gene-diet interaction effects were observed for other features of the MS. The age-and sex-adjusted odds ratio (OR) of exhibiting three or more features of the MS when carrying the À87C allele was 0.62 (P ¼ 0.04) compared to -87T/T. However, in subjects consuming less than 34.4% of energy from fat (median of fat consumption), the OR in carriers of the À87C allele was of 0.42 (P ¼ 0.008). Conclusion: These data suggest that the PPAR-delta À87T4C polymorphism may be associated with a lower risk to exhibit the MS and this association is influenced by dietary fat intake.

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Impaired skin wound healing in peroxisome proliferator–activated receptor (PPAR)α and PPARβ mutant mice

Cited by 383 publications

References 52 publications

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

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