Publications by authors named "Pascal G P Martin"

29 Publications

  • Page 1 of 1

The 7SK/P-TEFb snRNP controls ultraviolet radiation-induced transcriptional reprogramming.

Cell Rep 2021 Apr;35(2):108965

Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France. Electronic address:

Conversion of promoter-proximally paused RNA polymerase II (RNAPII) into elongating polymerase by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of mRNA synthesis. The activity of P-TEFb is controlled mainly by the 7SK small nuclear ribonucleoprotein (snRNP), which sequesters active P-TEFb into inactive 7SK/P-TEFb snRNP. Here we demonstrate that under normal culture conditions, the lack of 7SK snRNP has only minor impacts on global RNAPII transcription without detectable consequences on cell proliferation. However, upon ultraviolet (UV)-light-induced DNA damage, cells lacking 7SK have a defective transcriptional response and reduced viability. Both UV-induced release of "lesion-scanning" polymerases and activation of key early-responsive genes are compromised in the absence of 7SK. Proper induction of 7SK-dependent UV-responsive genes requires P-TEFb activity directly mobilized from the nucleoplasmic 7SK/P-TEFb snRNP. Our data demonstrate that the primary function of the 7SK/P-TEFb snRNP is to orchestrate the proper transcriptional response to stress.
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http://dx.doi.org/10.1016/j.celrep.2021.108965DOI Listing
April 2021

Transcriptomic modifications of the thyroid gland upon exposure to phytosanitary-grade fipronil: Evidence for the activation of compensatory pathways.

Toxicol Appl Pharmacol 2020 01 24;389:114873. Epub 2019 Dec 24.

ToxAlim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 180 chemin de Tournefeuille, BP93173, F-31027 Toulouse Cedex 03, France. Electronic address:

Fipronil is a phenylpyrazole insecticide used for the control of a variety of pest for domestic, veterinary and agricultural uses. Fipronil exposure is associated to thyroid disruption in the rat. It increases thyroid hormone (TH) hepatic clearance. The effect on thyroxine (T4) clearance is about four fold higher than the effect on T4 plasma concentrations suggesting that the thyroid gland might develop compensatory mechanisms. The aim of this study was to document the potential effects of fipronil treatment on the thyroid transcriptome together with its effects on TSH and TH blood levels under well characterized internal exposure to fipronil and its main metabolite fipronil sulfone. Fipronil (3 mg/kg/d by gavage for 14 days) clearance increased while its half-life decreased (about 10 fold) throughout treatment. Fipronil treatment in adult female rats significantly decreased total T4 and free triiodothyronine (T3) concentrations. Key genes related to thyroid hormone synthesis and/or cellular dynamic were modulated by fipronil exposure. RT-PCR confirmed that thyroglobulin gene expression was upregulated. A trend toward higher Na/I symporter expression was also noted, while sulfotransferase 1a1 gene expression was down-regulated. The expression of genes potentially involved in thyroid cell dynamic were upregulated (e.g. prostaglandin synthase 1, amphiregulin and Rhoa). Our results indicate that both pathways of TH synthesis and thyroid cell dynamics are transcriptional targets of fipronil and/or its main sulfone metabolite. The underlying mechanisms remain to be elucidated.
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http://dx.doi.org/10.1016/j.taap.2019.114873DOI Listing
January 2020

Co-occurrence of DON and Emerging Mycotoxins in Worldwide Finished Pig Feed and Their Combined Toxicity in Intestinal Cells.

Toxins (Basel) 2019 12 11;11(12). Epub 2019 Dec 11.

Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 180 Chemin de Tournefeuille, F- 31027 Toulouse CEDEX 3, France.

Food and feed can be naturally contaminated by several mycotoxins, and concern about the hazard of exposure to mycotoxin mixtures is increasing. In this study, more than 800 metabolites were analyzed in 524 finished pig feed samples collected worldwide. Eighty-eight percent of the samples were co-contaminated with deoxynivalenol (DON) and other regulated/emerging mycotoxins. The Top 60 emerging/regulated mycotoxins co-occurring with DON in pig feed shows that 48%, 13%, 8% and 12% are produced by Fusarium, Aspergillus, Penicillium and Alternaria species, respectively. Then, the individual and combined toxicity of DON and the 10 most prevalent emerging mycotoxins (brevianamide F, cyclo-(L-Pro-L-Tyr), tryptophol, enniatins A1, B, B1, emodin, aurofusarin, beauvericin and apicidin) was measured at three ratios corresponding to pig feed contamination. Toxicity was assessed by measuring the viability of intestinal porcine epithelial cells, IPEC-1, at 48-h. BRV-F, Cyclo and TRPT did not alter cell viability. The other metabolites were ranked in the following order of toxicity: apicidin > enniatin A1 > DON > beauvericin > enniatin B > enniatin B1 > emodin > aurofusarin. In most of the mixtures, combined toxicity was similar to the toxicity of DON alone. In terms of pig health, these results demonstrate that the co-occurrence of emerging mycotoxins that we tested with DON does not exacerbate toxicity.
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http://dx.doi.org/10.3390/toxins11120727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950336PMC
December 2019

BORDER proteins protect expression of neighboring genes by promoting 3' Pol II pausing in plants.

Nat Commun 2019 09 25;10(1):4359. Epub 2019 Sep 25.

Department of Biology, Indiana University, 915 East Third Street, Bloomington, IN, 47405, USA.

Ensuring that one gene's transcription does not inappropriately affect the expression of its neighbors is a fundamental challenge to gene regulation in a genomic context. In plants, which lack homologs of animal insulator proteins, the mechanisms that prevent transcriptional interference are not well understood. Here we show that BORDER proteins are enriched in intergenic regions and prevent interference between closely spaced genes on the same strand by promoting the 3' pausing of RNA polymerase II at the upstream gene. In the absence of BORDER proteins, 3' pausing associated with the upstream gene is reduced and shifts into the promoter region of the downstream gene. This is consistent with a model in which BORDER proteins inhibit transcriptional interference by preventing RNA polymerase from intruding into the promoters of downstream genes.
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http://dx.doi.org/10.1038/s41467-019-12328-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761125PMC
September 2019

NO synthesis from arginine is favored by α-linolenic acid in mice fed a high-fat diet.

Amino Acids 2016 09 13;48(9):2157-68. Epub 2016 May 13.

UMR Physiologie de la Nutrition et du Comportement Alimentaire, AgroParisTech, INRA, Université Paris-Saclay, 75005, Paris, France.

Alterations in NO availability and signaling play a pivotal role at early stages of the metabolic syndrome (MetSynd). We hypothesized that dietary α-linolenic acid (ALA, 18:3 n-3) favors NO availability by modulating amino acid metabolism, with a specific impact on the arginine-NO pathway. Mice were fed a hyperlipidic diet (285 g lipid/kg, 51.1 % energy), rich in either saturated fatty acids (SFA, provided by palm oil, PALM group) or ALA (provided by linseed oil, LIN group). We measured whole-body NO synthesis and systemic arginine hydrolysis with a tracer-based method, plasma concentration of related metabolites, and hepatic mRNA level of related enzymes, and the study was completed by a transcriptomic analysis in the liver. As expected with this model, hyperlipidic diets resulted in increased adiposity and glycemia after 5 weeks. As compared to PALM mice, LIN mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO vs urea, and a similar plasma concentration of asymmetric dimethylarginine (ADMA), despite a higher expression of the liver dimethylargininase-1. In LIN mice, there was a higher expression of genes involved in PPARα signaling, but a little impact on gene expression related to amino acids and arginine metabolism. This effect cannot be directly ascribed to changes in arginase activity in the liver or ADMA metabolism, nor to direct regulation of the related target genes. In conclusion, dietary ALA favors NO synthesis, which could contribute to rescue NO availability when jeopardized by the nutritional conditions in relation with the initiation of the MetSynd.
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http://dx.doi.org/10.1007/s00726-016-2243-yDOI Listing
September 2016

Exploring transcriptomic diversity in muscle revealed that cellular signaling pathways mainly differentiate five Western porcine breeds.

BMC Genomics 2015 Dec 12;16:1055. Epub 2015 Dec 12.

INRA, UMR1388 Génétique, Physiologie et Systèmes d'Elevage, F-31326, Castanet-Tolosan, France.

Background: Among transcriptomic studies, those comparing species or populations can increase our understanding of the impact of the evolutionary forces on the differentiation of populations. A particular situation is the one of short evolution time with breeds of a domesticated species that underwent strong selective pressures. In this study, the gene expression diversity across five pig breeds has been explored in muscle. Samples came from: 24 Duroc, 33 Landrace, 41 Large White dam line, 10 Large White sire line and 39 Piétrain. From these animals, 147 muscle samples obtained at slaughter were analyzed using the porcine Agilent 44 K v1 microarray.

Results: A total of 12,358 genes were identified as expressed in muscle after normalization and 1,703 genes were declared differential for at least one breed (FDR < 0.001). The functional analysis highlighted that gene expression diversity is mainly linked to cellular signaling pathways such as the PI3K (phosphoinositide 3-kinase) pathway. The PI3K pathway is known to be involved in the control of development of the skeletal muscle mass by affecting extracellular matrix - receptor interactions, regulation of actin cytoskeleton pathways and some metabolic functions. This study also highlighted 228 spots (171 unique genes) that differentiate the breeds from each other. A common subgroup of 15 genes selected by three statistical methods was able to differentiate Duroc, Large White and Piétrain breeds.

Conclusions: This study on transcriptomic differentiation across Western pig breeds highlighted a global picture: mainly signaling pathways were affected. This result is consistent with the selection objective of increasing muscle mass. These transcriptional changes may indicate selection pressure or simply breed differences which may be driven by human selection. Further work aiming at comparing genetic and transcriptomic diversities would further increase our understanding of the consequences of human impact on livestock species.
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http://dx.doi.org/10.1186/s12864-015-2259-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676870PMC
December 2015

The Extent of mRNA Editing Is Limited in Chicken Liver and Adipose, but Impacted by Tissular Context, Genotype, Age, and Feeding as Exemplified with a Conserved Edited Site in COG3.

G3 (Bethesda) 2015 Dec 4;6(2):321-35. Epub 2015 Dec 4.

Agrocampus Ouest, Unité Mixte de Recherche 1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Élevage, F-35000 Rennes, France Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Élevage, F-35000 Rennes, France

RNA editing is a posttranscriptional process leading to differences between genomic DNA and transcript sequences, potentially enhancing transcriptome diversity. With recent advances in high-throughput sequencing, many efforts have been made to describe mRNA editing at the transcriptome scale, especially in mammals, yielding contradictory conclusions regarding the extent of this phenomenon. We show, by detailed description of the 25 studies focusing so far on mRNA editing at the whole-transcriptome scale, that systematic sequencing artifacts are considered in most studies whereas biological replication is often neglected and multi-alignment not properly evaluated, which ultimately impairs the legitimacy of results. We recently developed a rigorous strategy to identify mRNA editing using mRNA and genomic DNA sequencing, taking into account sequencing and mapping artifacts, and biological replicates. We applied this method to screen for mRNA editing in liver and white adipose tissue from eight chickens and confirm the small extent of mRNA recoding in this species. Among the 25 unique edited sites identified, three events were previously described in mammals, attesting that this phenomenon is conserved throughout evolution. Deeper investigations on five sites revealed the impact of tissular context, genotype, age, feeding conditions, and sex on mRNA editing levels. More specifically, this analysis highlighted that the editing level at the site located on COG3 was strongly regulated by four of these factors. By comprehensively characterizing the mRNA editing landscape in chickens, our results highlight how this phenomenon is limited and suggest regulation of editing levels by various genetic and environmental factors.
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http://dx.doi.org/10.1534/g3.115.022251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751552PMC
December 2015

Muscle transcriptomic investigation of late fetal development identifies candidate genes for piglet maturity.

BMC Genomics 2014 Sep 17;15:797. Epub 2014 Sep 17.

INRA, UMR1388 Génétique, Physiologie et Systèmes d' Elevage, F-31326 Castanet-Tolosan, France.

Background: In pigs, the perinatal period is the most critical time for survival. Piglet maturation, which occurs at the end of gestation, leads to a state of full development after birth. Therefore, maturity is an important determinant of early survival. Skeletal muscle plays a key role in adaptation to extra-uterine life, e.g. glycogen storage and thermoregulation. In this study, we performed microarray analysis to identify the genes and biological processes involved in piglet muscle maturity. Progeny from two breeds with extreme muscle maturity phenotypes were analyzed at two time points during gestation (gestational days 90 and 110). The Large White (LW) breed is a selected breed with an increased rate of mortality at birth, whereas the Meishan (MS) breed produces piglets with extremely low mortality at birth. The impact of the parental genome was analyzed with reciprocal crossed fetuses.

Results: Microarray analysis identified 12,326 differentially expressed probes for gestational age and genotype. Such a high number reflects an important transcriptomic change that occurs between 90 and 110 days of gestation. 2,000 probes, corresponding to 1,120 unique annotated genes, involved more particularly in the maturation process were further studied. Functional enrichment and graph inference studies underlined genes involved in muscular development around 90 days of gestation, and genes involved in metabolic functions, such as gluconeogenesis, around 110 days of gestation. Moreover, a difference in the expression of key genes, e.g. PCK2, LDHA or PGK1, was detected between MS and LW just before birth. Reciprocal crossing analysis resulted in the identification of 472 genes with an expression preferentially regulated by one parental genome. Most of these genes (366) were regulated by the paternal genome. Among these paternally regulated genes, some known imprinted genes, such as MAGEL2 or IGF2, were identified and could have a key role in the maturation process.

Conclusion: These results reveal the biological mechanisms that regulate muscle maturity in piglets. Maturity is also under the conflicting regulation of the parental genomes. Crucial genes, which could explain the biological differences in maturity observed between LW and MS breeds, were identified. These genes could be excellent candidates for a key role in the maturity.
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http://dx.doi.org/10.1186/1471-2164-15-797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287105PMC
September 2014

The miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 domain controls neonatal metabolic adaptation.

EMBO J 2014 Oct 14;33(19):2216-30. Epub 2014 Aug 14.

Laboratoire de Biologie Moléculaire Eucaryote, UPS Université de Toulouse, Toulouse, France CNRS LBME, UMR5099, Toulouse, France

In mammals, birth entails complex metabolic adjustments essential for neonatal survival. Using a mouse knockout model, we identify crucial biological roles for the miR-379/miR-410 cluster within the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 locus, also named C14MC in humans, is the largest known placental mammal-specific miRNA cluster, whose 39 miRNA genes are expressed only from the maternal allele. We found that heterozygote pups with a maternal--but not paternal--deletion of the miRNA cluster display partially penetrant neonatal lethality with defects in the maintenance of energy homeostasis. This maladaptive metabolic response is caused, at least in part, by profound changes in the activation of the neonatal hepatic gene expression program, pointing to as yet unidentified regulatory pathways that govern this crucial metabolic transition in the newborn's liver. Not only does our study highlight the physiological importance of miRNA genes that recently evolved in placental mammal lineages but it also unveils additional layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on metabolic control at birth and have likely contributed to mammal evolution.
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http://dx.doi.org/10.15252/embj.201387038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282508PMC
October 2014

Changes in intestinal glucocorticoid sensitivity in early life shape the risk of epithelial barrier defect in maternal-deprived rats.

PLoS One 2014 20;9(2):e88382. Epub 2014 Feb 20.

Intestinal Development, Xenobiotics & Immunotoxicology, Institut National de la Recherche Agronomique (INRA), Research Centre in Food Toxicology (Toxalim), Toulouse, France.

Glucocorticoids (GC) contribute to human intestine ontogeny and accelerate gut barrier development in preparation to birth. Rat gut is immature at birth, and high intestinal GC sensitivity during the first two weeks of life resembles that of premature infants. This makes suckling rats a model to investigate postpartum impact of maternal separation (MS)-associated GC release in preterm babies, and whether GC sensitivity may shape MS effects in immature gut. A 4 hours-MS applied once at postnatal day (PND)10 enhanced plasma corticosterone in male and female pups, increased by two times the total in vivo intestinal permeability (IP) to oral FITC-Dextran 4 kDa (FD4) immediately after the end of MS, and induced bacterial translocation (BT) to liver and spleen. Ussing chamber experiments demonstrated a 2-fold increase of permeability to FD4 in the colon immediately after the end of MS, but not in the ileum. Colonic permeability was not only increased for FD4 but also to intact horseradish peroxidase 44 kDa in MS pups. In vivo, the glucocorticoid receptor (GR) antagonist RU486 or ML7 blockade of myosin light chain kinase controlling epithelial cytoskeleton contraction prevented MS-induced IP increase to oral FD4 and BT. In addition, the GR agonist dexamethasone dose-dependently mimicked MS-increase of IP to oral FD4. In contrast, MS effects on IP to oral FD4 and BT were absent at PND20, a model for full-term infant, characterized by a marked drop of IP to FD4 in response to dexamethasone, and decreased GR expression in the colon only compared to PND10 pups. These results show that high intestinal GC responsiveness in a rat model of prematurity defines a vulnerable window for a post-delivery MS, evoking immediate disruption of epithelial integrity in the large intestine, and increasing susceptibility to macromolecule passage and bacteremia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930527PMC
January 2015

Chromatin immunoprecipitation indirect peaks highlight long-range interactions of insulator proteins and Pol II pausing.

Mol Cell 2014 Feb 30;53(4):672-81. Epub 2014 Jan 30.

Laboratoire de Biologie Moléculaire Eucaryote (LBME), CNRS, Université de Toulouse (UPS), 31000 Toulouse, France. Electronic address:

Eukaryotic chromosomes are partitioned into topologically associating domains (TADs) that are demarcated by distinct insulator-binding proteins (IBPs) in Drosophila. Whether IBPs regulate specific long-range contacts and how this may impact gene expression remains unclear. Here we identify "indirect peaks" of multiple IBPs that represent their distant sites of interactions through long-range contacts. Indirect peaks depend on protein-protein interactions among multiple IBPs and their common cofactors, including CP190, as confirmed by high-resolution analyses of long-range contacts. Mutant IBPs unable to interact with CP190 impair long-range contacts as well as the expression of hundreds of distant genes that are specifically flanked by indirect peaks. Regulation of distant genes strongly correlates with RNAPII pausing, highlighting how this key transcriptional stage may trap insulator-based long-range interactions. Our data illustrate how indirect peaks may decipher gene regulatory networks through specific long-range interactions.
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http://dx.doi.org/10.1016/j.molcel.2013.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198380PMC
February 2014

The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.

Biochem Pharmacol 2013 Oct 17;86(7):997-1039. Epub 2013 Aug 17.

INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France; Université de Toulouse, ENVT, INP, Toxalim, F-31076 Toulouse, France.

Fipronil is described as a thyroid disruptor in rat. Based on the hypothesis that this results from a perturbation of hepatic thyroid hormone metabolism, our goal was to investigate the pathways involved in fipronil-induced liver gene expression regulations. First, we performed a microarray screening in the liver of rats treated with fipronil or vehicle. Fipronil treatment led to the upregulation of several genes involved in the metabolism of xenobiotics, including the cytochrome P450 Cyp2b1, Cyp2b2 and Cyp3a1, the carboxylesterases Ces2 and Ces6, the phase II enzymes Ugt1a1, Sult1b1 and Gsta2, and the membrane transporters Abcc2, Abcc3, Abcg5, Abcg8, Slco1a1 and Slco1a4. Based on a large overlap with the target genes of constitutive androstane receptor (CAR) and pregnane X receptor (PXR), we postulated that these two nuclear receptors are involved in mediating the effects of fipronil on liver gene expression in rodents. We controlled that liver gene expression changes induced by fipronil were generally reproduced in mice, and then studied the effects of fipronil in wild-type, CAR- and PXR-deficient mice. For most of the genes studied, the gene expression modulations were abolished in the liver of PXR-deficient mice and were reduced in the liver of CAR-deficient mice. However, CAR and PXR activation in mouse liver was not associated with a marked increase of thyroid hormone clearance, as observed in rat. Nevertheless, our data clearly indicate that PXR and CAR are key modulators of the hepatic gene expression profile following fipronil treatment which, in rats, may contribute to increase thyroid hormone clearance.
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http://dx.doi.org/10.1016/j.bcp.2013.08.012DOI Listing
October 2013

Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor.

J Hepatol 2013 May 16;58(5):984-92. Epub 2013 Jan 16.

INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France.

Background & Aims: Nutrients influence non-alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes, including hepatic steatosis, through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified.

Methods: We used wild type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors.

Results: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency.

Conclusions: This work identifies, for the first time, the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.
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http://dx.doi.org/10.1016/j.jhep.2013.01.006DOI Listing
May 2013

A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARα.

Biochimie 2013 Mar 10;95(3):556-67. Epub 2012 Oct 10.

INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, Université de Toulouse, Toulouse, France.

The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.
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http://dx.doi.org/10.1016/j.biochi.2012.09.028DOI Listing
March 2013

Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver.

Hepatology 2012 Feb 22;55(2):395-407. Epub 2011 Dec 22.

INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France.

Unlabelled: Changes in lifestyle are suspected to have strongly influenced the current obesity epidemic. Based on recent experimental, clinical, and epidemiological work, it has been proposed that some food contaminants may exert damaging effects on endocrine and metabolic functions, thereby promoting obesity and associated metabolic diseases such as nonalcoholic fatty liver disease (NAFLD). In this work, we investigated the effect of one suspicious food contaminant, bisphenol A (BPA), in vivo. We used a transcriptomic approach in male CD1 mice exposed for 28 days to different doses of BPA (0, 5, 50, 500, and 5,000 μg/kg/day) through food contamination. Data analysis revealed a specific impact of low doses of BPA on the hepatic transcriptome, more particularly on genes involved in lipid synthesis. Strikingly, the effect of BPA on the expression of de novo lipogenesis followed a nonmonotonic dose-response curve, with more important effects at lower doses than at the higher dose. In addition to lipogenic enzymes (Acc, Fasn, Scd1), the expression of transcription factors such as liver X Receptor, the sterol regulatory element binding protein-1c, and the carbohydrate responsive element binding protein that govern the expression of lipogenic genes also followed a nonmonotonic dose-response curve in response to BPA. Consistent with an increased fatty acid biosynthesis, determination of fat in the liver showed an accumulation of cholesteryl esters and of triglycerides.

Conclusion: Our work suggests that exposure to low BPA doses may influence de novo fatty acid synthesis through increased expression of lipogenic genes, thereby contributing to hepatic steatosis. Exposure to such contaminants should be carefully examined in the etiology of metabolic diseases such as NAFLD and nonalcoholic steatohepatitis.
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http://dx.doi.org/10.1002/hep.24685DOI Listing
February 2012

A role for PPARα in the regulation of arginine metabolism and nitric oxide synthesis.

Amino Acids 2011 Oct 10;41(4):969-79. Epub 2010 Nov 10.

UMR914 Nutrition Physiology and Ingestive Behavior, INRA, 16 rue Claude Bernard, 75005, Paris, France.

The pleiotropic effects of PPARα may include the regulation of amino acid metabolism. Nitric oxide (NO) is a key player in vascular homeostasis. NO synthesis may be jeopardized by a differential channeling of arginine toward urea (via arginase) versus NO (via NO synthase, NOS). This was studied in wild-type (WT) and PPARα-null (KO) mice fed diets containing either saturated fatty acids (COCO diet) or 18:3 n-3 (LIN diet). Metabolic markers of arginine metabolism were assayed in urine and plasma. mRNA levels of arginases and NOS were determined in liver. Whole-body NO synthesis and the conversion of systemic arginine into urea were assessed by using (15)N(2)-guanido-arginine and measuring urinary (15)NO(3) and [(15)N]-urea. PPARα deficiency resulted in a markedly lower whole-body NO synthesis, whereas the conversion of systemic arginine into urea remained unaffected. PPARα deficiency also increased plasma arginine and decreased citrulline concentration in plasma. These changes could not be ascribed to a direct effect on hepatic target genes, since NOS mRNA levels were unaffected, and arginase mRNA levels decreased in KO mice. Despite the low level in the diet, the nature of the fatty acids modulated some effects of PPARα deficiency, including plasma arginine and urea, which increased more in KO mice fed the LIN diet than in those fed the COCO diet. In conclusion, PPARα is largely involved in normal whole-body NO synthesis. This warrants further study on the potential of PPARα activation to maintain NO synthesis in the initiation of the metabolic syndrome.
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http://dx.doi.org/10.1007/s00726-010-0797-7DOI Listing
October 2011

FAN (factor associated with neutral sphingomyelinase activation), a moonlighting protein in TNF-R1 signaling.

J Leukoc Biol 2010 Nov 9;88(5):897-903. Epub 2010 Jun 9.

Institut de Médecine Moléculaire de Rangueil, Toulouse Cédex 4, France.

TNF-α is a pleiotropic cytokine involved in the regulation of various biological effects, including cell survival and proliferation, cell differentiation, and cell death. Moreover, TNF-α triggers proinflammatory responses, essentially through its ability to promote the expression of various proinflammatory genes. Most of the biological effects initiated by TNF-α rely on its ability to bind to and activate TNF-R1. As a consequence, molecular complexes are being formed, resulting from the recruitment of multiple adaptor proteins to the intracellular TNF-R1 DD. The adaptor protein FAN constitutively binds to a proximal membrane domain of TNF-R1 called NSD. Herein, the role of FAN in TNF-α-induced cell signaling and biological responses is discussed.
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http://dx.doi.org/10.1189/jlb.0410188DOI Listing
November 2010

The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice.

Prog Lipid Res 2010 Apr 16;49(2):186-99. Epub 2009 Dec 16.

Integrative Toxicology and Metabolism, Pôle de Toxicologie Alimentaire, Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique INRA UR66, Toulouse Cedex 3, France.

In mammalian cells, elongases and desaturases play critical roles in regulating the length and degree of unsaturation of fatty acids and thereby their functions and metabolic fates. In the past decade, a great deal has been learnt about these enzymes and the first part of this review summarizes our current knowledge concerning these enzymes. More recently, several transgenic mouse models lacking either an elongase (Elovl3(-/-), Elovl4(-/-), Elovl5(-/-), Elovl6(-/-)) or a desaturase (Scd-1(-/-), Scd-2(-/-), Fads2(-/-)) have been developed and the second part of this review focuses on the insights gained from studies with these mice, as well as from investigations on cell cultures.
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http://dx.doi.org/10.1016/j.plipres.2009.12.002DOI Listing
April 2010

FAN stimulates TNF(alpha)-induced gene expression, leukocyte recruitment, and humoral response.

J Immunol 2009 Oct 28;183(8):5369-78. Epub 2009 Sep 28.

U858 INSERM, Toulouse, France.

Factor associated with neutral sphingomyelinase activation (FAN) is an adaptor protein that constitutively binds to TNF-R1. Microarray analysis was performed in fibroblasts derived from wild-type or FAN knockout mouse embryos to evaluate the role of FAN in TNF-induced gene expression. Approximately 70% of TNF-induced genes exhibited lower expression levels in FAN-deficient than in wild-type fibroblasts. Of particular interest, TNF-induced expression of cytokines/chemokines, such as IL-6 and CXCL-2, was impaired in FAN-deficient cells. This was confirmed by real time RT-PCR and ELISA. Upon i.p. TNF or thioglycollate injection, neutrophil recruitment into the peritoneal cavity was reduced by more than 50% in FAN-deficient mice. Nevertheless, FAN-deficient animals did not exhibit an increased susceptibility to different microorganisms including bacteria and parasites, indicating that FAN is not essential for pathogen clearance. Specific Ab response to BSA was substantially impaired in FAN-deficient mice and this was associated with a reduced content of leukocytes in the spleen of BSA-challenged FAN-deficient mice as compared with their wild-type counterparts. Altogether, our results indicate the involvement of FAN in TNF-induced gene expression and leukocyte recruitment, contributing to the establishment of the specific immune response.
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http://dx.doi.org/10.4049/jimmunol.0803384DOI Listing
October 2009

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): a novel signalling pathway sensitive to phthalates.

Biochem Pharmacol 2009 Jun 11;77(11):1735-46. Epub 2009 Mar 11.

Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, INRA UR66, Toulouse, France.

Di-(2-ethylhexyl)-phthalate (DEHP), a widely used plasticizer, is detected in consumer's body fluids. Contamination occurs through environmental and food chain sources. In mouse liver, DEHP activates the peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates the expression of its target genes. Several in vitro investigations support the simultaneous recruitment of additional nuclear receptor pathways. We investigated, in vivo, the hepatic impact of low doses of DEHP on PPARalpha activation, and the putative activation of additional signalling pathways. Wild-type and PPARalpha-deficient mice were exposed to different doses of DEHP. Gene expression profiling delineated the role of PPARalpha and revealed a PPARalpha-independent regulation of several prototypic constitutive androstane receptor (CAR) target genes. Thus, we developed an original hepatic cell line expressing CAR to investigate its activation by DEHP. By means of a pharmacological inhibitor or CAR-targeting shRNAs, we established that CAR is required for the effect of DEHP on Cyp2b10, a recognized CAR target gene. Moreover, DEHP dose-dependently induced CYP2B6 in human primary hepatocyte cultures. This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome.
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http://dx.doi.org/10.1016/j.bcp.2009.02.023DOI Listing
June 2009

Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach.

Toxicol Appl Pharmacol 2009 May 23;236(3):282-92. Epub 2009 Feb 23.

Pôle de Toxicologie Alimentaire, Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique INRA UR66, Toulouse Cedex 3, France.

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.
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http://dx.doi.org/10.1016/j.taap.2009.02.008DOI Listing
May 2009

Sparse canonical methods for biological data integration: application to a cross-platform study.

BMC Bioinformatics 2009 Jan 26;10:34. Epub 2009 Jan 26.

Station d'Amélioration Génétique des Animaux UR 631, Institut National de Recherche Agronomique, F-31326 Castanet, France.

Background: In the context of systems biology, few sparse approaches have been proposed so far to integrate several data sets. It is however an important and fundamental issue that will be widely encountered in post genomic studies, when simultaneously analyzing transcriptomics, proteomics and metabolomics data using different platforms, so as to understand the mutual interactions between the different data sets. In this high dimensional setting, variable selection is crucial to give interpretable results. We focus on a sparse Partial Least Squares approach (sPLS) to handle two-block data sets, where the relationship between the two types of variables is known to be symmetric. Sparse PLS has been developed either for a regression or a canonical correlation framework and includes a built-in procedure to select variables while integrating data. To illustrate the canonical mode approach, we analyzed the NCI60 data sets, where two different platforms (cDNA and Affymetrix chips) were used to study the transcriptome of sixty cancer cell lines.

Results: We compare the results obtained with two other sparse or related canonical correlation approaches: CCA with Elastic Net penalization (CCA-EN) and Co-Inertia Analysis (CIA). The latter does not include a built-in procedure for variable selection and requires a two-step analysis. We stress the lack of statistical criteria to evaluate canonical correlation methods, which makes biological interpretation absolutely necessary to compare the different gene selections. We also propose comprehensive graphical representations of both samples and variables to facilitate the interpretation of the results.

Conclusion: sPLS and CCA-EN selected highly relevant genes and complementary findings from the two data sets, which enabled a detailed understanding of the molecular characteristics of several groups of cell lines. These two approaches were found to bring similar results, although they highlighted the same phenomenons with a different priority. They outperformed CIA that tended to select redundant information.
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http://dx.doi.org/10.1186/1471-2105-10-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640358PMC
January 2009

Effects of dexamethasone, administered for growth promoting purposes, upon the hepatic cytochrome P450 3A expression in the veal calf.

Biochem Pharmacol 2009 Feb 31;77(3):451-63. Epub 2008 Oct 31.

Dipartimento di Patologia Animale, sezione di Farmacologia e Tossicologia, Università di Torino, via Leonardo da Vinci 44, I-10095 Grugliasco (Torino), Italy.

Dexamethasone (DEX) exerts its known anti-inflammatory and immunosuppressant activities through the interaction with the glucocorticoid receptor (GR). In human liver, DEX is metabolized by cytochrome P450 3A (CYP3A); moreover, it is among those xenobiotics which induce CYP3A itself. The transcriptional regulation of CYP3A involves GR and nuclear receptors (NRs). In cattle, DEX is used at low dosages as a growth promoter; besides, CYP3A is expressed in the liver. In the present study, the effects of two illicit DEX protocols upon liver CYP3A were investigated in the veal calf. Dexamethasone, administered per os (DOS) or injected intramuscularly (DIM) at growth promoting purposes, increased GR mRNA (+25.62% and +73.02% of CTRL for DOS and DIM, respectively), while tyrosine aminotransferase (TAT) and NRs gene expression profiles were unaffected; decreased CYP3A mRNA (-20.64% and -16.07% with Q RT-PCR; -30.55% and -34.31% with Northern blotting); at the post-translational level, decreased TAT activity (-19.84% and 44.34%), CYP3A apoprotein (-27.65% and -42.85%) and CYP3A-dependent enzyme activities (erythromycin N-demethylase, -78.89% and -23.87%; ethylmorphine N-demethylase, -44.26% and -28.37%; testosterone 6beta-hydroxylase, -44.60% and -18.07%; testosterone 2beta-hydroxylase, -43.95% and -11.69%); by contrast, an increase (about 2-fold) of the urinary 6beta-hydroxycortisol:cortisol ratio was observed in vivo. In summary, DEX modulates cattle liver CYP3A at pre- and post-translational level. Species-differences in GR-NRs-CYP3A regulation and in their response to differing DEX dosages might justify present results. Furthermore, the urinary 6beta-hydroxycortisol:cortisol ratio is not useful to monitor in vivo CYP3A activity in DEX-treated individuals.
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http://dx.doi.org/10.1016/j.bcp.2008.10.025DOI Listing
February 2009

Transcriptional regulation of hepatic fatty acid metabolism.

Subcell Biochem 2008 ;49:3-47

Laboratoire de Pharmacologie et Toxicologie UR66, INRA, F-3100 Toulouse, France.

The liver is a major site of fatty acid synthesis and degradation. Transcriptional regulation is one of several mechanisms controlling hepatic metabolism of fatty acids. Two transcription factors, namely SREBP1-c and PPARalpha, appear to be the main players controlling synthesis and degradation of fatty acids respectively. This chapter briefly presents fatty acid metabolism. The first part focuses on SREBP1-c contribution to the control of gene expression relevant to fatty acid synthesis and the main mechanisms of activation for this transcriptional program. The second part reviews the evidence for the involvement of PPARalpha in the control of fatty acid degradation and the key features of this nuclear receptor. Finally, the third part aims at summarizing recent advances in our current understanding of how these two transcription factors fit in the regulatory networks that sense hormones or nutrients, including cellular fatty acids, and govern the transcription of genes implicated in hepatic fatty acid metabolism.
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http://dx.doi.org/10.1007/978-1-4020-8831-5_1DOI Listing
December 2008

Cytochrome P450 inhibition profile in liver of veal calves administered a combination of 17beta-estradiol, clenbuterol, and dexamethasone for growth-promoting purposes.

Food Chem Toxicol 2008 Aug 29;46(8):2849-55. Epub 2008 May 29.

Dipartimento di Patologia Animale, Sezione di Farmacologia e Tossicologia, Università di Torino, Via Leonardo da Vinci 44, 10095 Grugliasco (TO), Italy.

The effects of the administration of a combination of 17beta-estradiol (10mg i.m. for three times at 17 days intervals), dexamethasone (4 mg/day for 6 days and 5mg/day for further 6 days, dissolved in milk), and clenbuterol (20 microg/kg b.w./day, dissolved in milk, for the last 40 days before slaughtering) for growth-promoting (GP) purposes on liver drug metabolising capacity were studied in crossbred Friesian male calves. Compared to controls, liver preparations from GP-treated calves showed an overall reduction in the extent of the in vitro ability to metabolize testosterone and a number of substrates, most notably those associated with CYP 2C or CYP 3A, which also displayed a reduced expression on western blotting. By contrast, the tested hydrolytic and conjugative pathways were not significantly affected. As measured by northern blot, the lack of significant differences in CYP mRNA abundance point to a post-transcriptional effect of the GP combination. The remarkable involvement of the affected hepatic CYPs in the biotransformation of both steroid hormones and a large array of commonly used drugs may result in the further accumulation of undesirable residues in meat and offals of illegally treated calves.
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http://dx.doi.org/10.1016/j.fct.2008.05.018DOI Listing
August 2008

High potency of bioactivation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mouse colon epithelial cells with Apc(Min) mutation.

Mutat Res 2008 May 15;653(1-2):34-43. Epub 2008 Mar 15.

INRA/ENVT, UMR1089 Laboratoire des Xénobiotiques, 180, Chemin de Tournefeuille, F-31931 Toulouse, France.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a prominent heterocyclic aromatic amine (HAA) found in meat and fish cooked at moderate to high temperature. It is considered as a potent dietary factor promoting colon carcinogenesis. However, the role of intestinal cells in PhIP bioactivation has not been fully explained, particularly when cells are pre-malignant. Loss of function of the adenomatous polyposis coli (APC) gene product is an early and frequent event in human colorectal carcinogenesis. Normal (Apc(+/+)) and pre-malignant (Apc(Min/+), where Min=multiple intestinal neoplasia) colonic epithelial cells of mice can be used to study promotion of carcinogenesis, but these cells have not been characterized for bio-activation of HAA. We investigated the metabolism of (14)C-PhIP in these two murine cell lines. Cells induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) metabolized PhIP into 4'-OH-PhIP as the main metabolite in PhiP detoxification. Besides, 5-OH-PhIP was identified, revealing the formation of intermediary reactive metabolites, since it results from a degradation of conjugates of N-acetoxy-PhIP. Apc(Min/+) cells produce significantly higher amounts of these metabolites. Demethylated metabolites are also observed, indicating that the colon contains a significant CYP1 family dependent metabolic activity. A minor hydroxy-glucuronide-PhIP metabolite is observed in Apc(Min/+) cells, the glucuronidation being known as an important step in the detoxification pathway. Quantitative real-time reverse transcription polymerase chain reaction experiments demonstrate that induction by TCDD has prevailing effects in gene expression of CYP1A1, CYP1A2 and CYP1B1 in Apc(Min/+) cells. In these cells, N-acetyltransferase-2 is also expressed at higher levels. So, the more important potency to metabolically bio-activate PhIP, as measured in Apc(Min/+) cells, can be linked to a higher probability to generate new in situ mutations.
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http://dx.doi.org/10.1016/j.mrgentox.2008.02.010DOI Listing
May 2008

Novel aspects of PPARalpha-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study.

Hepatology 2007 Mar;45(3):767-77

Laboratoire de Pharmacologie et Toxicologie UR66, INRA, F-31931 Toulouse, France.

Unlabelled: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a major transcriptional regulator of lipid metabolism. It is activated by diverse chemicals such as fatty acids (FAs) and regulates the expression of numerous genes in organs displaying high FA catabolic rates, including the liver. The role of this nuclear receptor as a sensor of whole dietary fat intake has been inferred, mostly from high-fat diet studies. To delineate its function under low fat intake conditions (4.8% w/w), we studied the effects of five regimens with contrasted FA compositions on liver lipids and hepatic gene expression in wild-type and PPARalpha-deficient mice. Diets containing polyunsaturated FAs reduced hepatic fat stores in wild-type mice. Only sunflower, linseed, and fish oil diets lowered hepatic lipid stores in PPARalpha-/- mice, a model of progressive hepatic triglyceride accumulation. These beneficial effects were associated, in particular, with dietary regulation of Delta9-desaturase in both genotypes, and with a newly identified PPARalpha-dependent regulation of lipin. Furthermore, hepatic levels of 18-carbon essential FAs (C18:2omega6 and C18:3omega3) were elevated in PPARalpha-/- mice, possibly due to the observed reduction in expression of the Delta6-desaturase and of enoyl-coenzyme A isomerases. Effects of diet and genotype were also observed on the xenobiotic metabolism-related genes Cyp3a11 and CAR.

Conclusion: Together, our results suggest that dietary FAs represent--even under low fat intake conditions--a beneficial strategy to reduce hepatic steatosis. Under such conditions, we established the role of PPARalpha as a dietary FA sensor and highlighted its importance in regulating hepatic FA content and composition.
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http://dx.doi.org/10.1002/hep.21510DOI Listing
March 2007

Transcriptional modulations by RXR agonists are only partially subordinated to PPARalpha signaling and attest additional, organ-specific, molecular cross-talks.

Gene Expr 2005 ;12(3):177-92

Laboratoire de Pharmacologie et Toxicologie, I.N.R.A., BP3, Toulouse, France.

Nuclear hormone receptors (NR) are important transcriptional regulators of numerous genes involved in diverse pathophysiological and therapeutic functions. Following ligand activation, class II NR share the ability to heterodimerize with the retinoid X receptor (RXR). It is established that RXR activators, rexinoids, transactivate several peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in a PPARalpha-dependent manner. We hypothesized that, once activated, RXR might signal through quiescent NR other than PPARalpha, in an organ-specific manner. To study this putative phenomenon in vivo, we developed an array of 120 genes relevant to the class II NR field. The genes were selected using both published data and high-density screenings performed on RXR or PPARalpha agonist-treated mice. Wild-type C57BL/6J and PPARalpha-deficient mice were treated with fenofibrate (PPARalpha activator) or LGD1069 (RXR activator). Using our customized array, we studied the hepatic, cardiac, and renal expression of this panel of 120 genes and compared them in both murine genotypes. The results obtained from this study confirmed the ability of an RXR agonist to modulate PPARalpha-restricted target genes in the liver and the kidney. Furthermore, we show that various organ-specific regulations occurring in both genotypes (PPARalpha +/+ or -/-) are highly indicative of the ability of RXR to recruit other class II NR pathways. Further development of this molecular tool may lead to a better understanding of the permissiveness of class II nuclear receptor dimers in vivo.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009114PMC
http://dx.doi.org/10.3727/000000005783992098DOI Listing
June 2006

Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator.

J Cell Biol 2005 Apr 4;169(1):93-104. Epub 2005 Apr 4.

Laboratoire de Biologie Moléculaire et Cellulaire, Faculté des Sciences Gabriel, 21000 Dijon, France.

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARalpha-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARalpha independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition.
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http://dx.doi.org/10.1083/jcb.200501036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171887PMC
April 2005