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Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.
Clémence Rives; Anne Fougerat; Sandrine Ellero-Simatos; Nicolas Loiseau; Hervé Guillou; Laurence Gamet-Payrastre; Walter Wahli. Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants. Biomolecules 2020, 10, 1702 .
AMA StyleClémence Rives, Anne Fougerat, Sandrine Ellero-Simatos, Nicolas Loiseau, Hervé Guillou, Laurence Gamet-Payrastre, Walter Wahli. Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants. Biomolecules. 2020; 10 (12):1702.
Chicago/Turabian StyleClémence Rives; Anne Fougerat; Sandrine Ellero-Simatos; Nicolas Loiseau; Hervé Guillou; Laurence Gamet-Payrastre; Walter Wahli. 2020. "Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants." Biomolecules 10, no. 12: 1702.
The Cytolethal Distending Toxin (CDT) is produced by many Gram-negative pathogenic bacteria responsible for major foodborne diseases worldwide. CDT induces DNA damage and cell cycle arrest in host-cells, eventually leading to senescence or apoptosis. According to structural and sequence comparison, the catalytic subunit CdtB is suggested to possess both nuclease and phosphatase activities, carried by a single catalytic site. However, the impact of each activity on cell-host toxicity is yet to be characterized. Here, we analyze the consequences of cell exposure to different CDT mutated on key CdtB residues, focusing on cell viability, cell cycle defects, and DNA damage induction. A first class of mutant, devoid of any activity, targets putative catalytic (H160A), metal binding (D273R), and DNA binding residues (R117A-R144A-N201A). The second class of mutants (A163R, F156-T158, and the newly identified G114T), which gathers mutations on residues potentially involved in lipid substrate binding, has only partially lost its toxic effects. However, their defects are alleviated when CdtB is artificially introduced inside cells, except for the F156-T158 double mutant that is defective in nuclear addressing. Therefore, our data reveal that CDT toxicity is mainly correlated to CdtB nuclease activity, whereas phosphatase activity may probably be involved in CdtB intracellular trafficking.
Benoît J. Pons; Nicolas Loiseau; Saleha Hashim; Soraya Tadrist; Gladys Mirey; Julien Vignard. Functional Study of Haemophilus ducreyi Cytolethal Distending Toxin Subunit B. Toxins 2020, 12, 530 .
AMA StyleBenoît J. Pons, Nicolas Loiseau, Saleha Hashim, Soraya Tadrist, Gladys Mirey, Julien Vignard. Functional Study of Haemophilus ducreyi Cytolethal Distending Toxin Subunit B. Toxins. 2020; 12 (9):530.
Chicago/Turabian StyleBenoît J. Pons; Nicolas Loiseau; Saleha Hashim; Soraya Tadrist; Gladys Mirey; Julien Vignard. 2020. "Functional Study of Haemophilus ducreyi Cytolethal Distending Toxin Subunit B." Toxins 12, no. 9: 530.
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
Anne Fougerat; Alexandra Montagner; Nicolas Loiseau; Hervé Guillou; Walter Wahli. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020, 9, 1638 .
AMA StyleAnne Fougerat, Alexandra Montagner, Nicolas Loiseau, Hervé Guillou, Walter Wahli. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells. 2020; 9 (7):1638.
Chicago/Turabian StyleAnne Fougerat; Alexandra Montagner; Nicolas Loiseau; Hervé Guillou; Walter Wahli. 2020. "Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease." Cells 9, no. 7: 1638.
Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα - deficient mice (Pparα −/− ) and in mice lacking Pparα only in hepatocytes (Pparα hep−/− ). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.
Marion Regnier; Arnaud Polizzi; Sarra Smati; Céline Lukowicz; Anne Fougerat; Yannick Lippi; Edwin Fouché; Frédéric Lasserre; Claire Naylies; Colette Bétoulières; Valentin Barquissau; Etienne Mouisel; Justine Bertrand-Michel; Aurélie Batut; Talal Al Saati; Cécile Canlet; Marie Tremblay-Franco; Sandrine Ellero-Simatos; Dominique Langin; Catherine Postic; Walter Wahli; Nicolas Loiseau; Hervé Guillou; Alexandra Montagner. Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity. Scientific Reports 2020, 10, 1 -15.
AMA StyleMarion Regnier, Arnaud Polizzi, Sarra Smati, Céline Lukowicz, Anne Fougerat, Yannick Lippi, Edwin Fouché, Frédéric Lasserre, Claire Naylies, Colette Bétoulières, Valentin Barquissau, Etienne Mouisel, Justine Bertrand-Michel, Aurélie Batut, Talal Al Saati, Cécile Canlet, Marie Tremblay-Franco, Sandrine Ellero-Simatos, Dominique Langin, Catherine Postic, Walter Wahli, Nicolas Loiseau, Hervé Guillou, Alexandra Montagner. Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity. Scientific Reports. 2020; 10 (1):1-15.
Chicago/Turabian StyleMarion Regnier; Arnaud Polizzi; Sarra Smati; Céline Lukowicz; Anne Fougerat; Yannick Lippi; Edwin Fouché; Frédéric Lasserre; Claire Naylies; Colette Bétoulières; Valentin Barquissau; Etienne Mouisel; Justine Bertrand-Michel; Aurélie Batut; Talal Al Saati; Cécile Canlet; Marie Tremblay-Franco; Sandrine Ellero-Simatos; Dominique Langin; Catherine Postic; Walter Wahli; Nicolas Loiseau; Hervé Guillou; Alexandra Montagner. 2020. "Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity." Scientific Reports 10, no. 1: 1-15.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Céline Lukowicz; Sandrine Ellero-Simatos; Marion Régnier; Fabiana Oliviero; Frédéric Lasserre; Arnaud Polizzi; Alexandra Montagner; Sarra Smati; Frédéric Boudou; Françoise Lenfant; Laurence Guzylack-Pirou; Sandrine Menard; Sharon Barretto; Anne Fougerat; Yannick Lippi; Claire Naylies; Justine Bertrand-Michel; Afifa Ait Belgnaoui; Vassilia Theodorou; Nicola Marchi; Pierre Gourdy; Laurence Gamet-Payrastre; Nicolas Loiseau; Hervé Guillou; Laïla Mselli-Lakhal. Author Correction: Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor. Scientific Reports 2020, 10, 4256 -2.
AMA StyleCéline Lukowicz, Sandrine Ellero-Simatos, Marion Régnier, Fabiana Oliviero, Frédéric Lasserre, Arnaud Polizzi, Alexandra Montagner, Sarra Smati, Frédéric Boudou, Françoise Lenfant, Laurence Guzylack-Pirou, Sandrine Menard, Sharon Barretto, Anne Fougerat, Yannick Lippi, Claire Naylies, Justine Bertrand-Michel, Afifa Ait Belgnaoui, Vassilia Theodorou, Nicola Marchi, Pierre Gourdy, Laurence Gamet-Payrastre, Nicolas Loiseau, Hervé Guillou, Laïla Mselli-Lakhal. Author Correction: Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor. Scientific Reports. 2020; 10 (1):4256-2.
Chicago/Turabian StyleCéline Lukowicz; Sandrine Ellero-Simatos; Marion Régnier; Fabiana Oliviero; Frédéric Lasserre; Arnaud Polizzi; Alexandra Montagner; Sarra Smati; Frédéric Boudou; Françoise Lenfant; Laurence Guzylack-Pirou; Sandrine Menard; Sharon Barretto; Anne Fougerat; Yannick Lippi; Claire Naylies; Justine Bertrand-Michel; Afifa Ait Belgnaoui; Vassilia Theodorou; Nicola Marchi; Pierre Gourdy; Laurence Gamet-Payrastre; Nicolas Loiseau; Hervé Guillou; Laïla Mselli-Lakhal. 2020. "Author Correction: Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor." Scientific Reports 10, no. 1: 4256-2.
Metabolic diseases such as obesity, type II diabetes and hepatic steatosis are a public health concern in developed countries. The metabolic risk is gender‐dependent. The constitutive androstane receptor (CAR), which is at the crossroads between energy metabolism and endocrinology, has recently emerged as a promising therapeutic agent for the treatment of obesity and type 2 diabetes. In this study we sought to determine its role in the dimorphic regulation of energy homeostasis. We tracked male and female WT and CAR deficient (CAR−/−) mice for over a year. During aging, CAR−/− male mice developed hypercortisism, obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis. Remarkably, the latter modifications were absent, or minor, in female CAR−/− mice. When ovariectomized, CAR−/− female mice developed identical patterns of metabolic disorders as observed in male mice. These results highlight the importance of steroid hormones in the regulation of energy metabolism by CAR. They unveil a sexually dimorphic role of CAR in the maintenance of endocrine and metabolic homeostasis underscoring the importance of considering sex in treatment of metabolic diseases.
Céline Lukowicz; Sandrine Ellero-Simatos; Marion Regnier; Fabiana Oliviero; Frédéric Lasserre; Arnaud Polizzi; Alexandra Montagner; Sarra Smati; Frédéric Boudou; Francoise Lenfant; Laurence Guzylack-Pirou; Sandrine Menard; Sharon Barretto; Anne Fougerat; Yannick Lippi; Claire Naylies; Justine Bertrand-Michel; Afifa Ait Belgnaoui; Vassilia Theodorou; Nicola Marchi; Pierre Gourdy; Laurence Gamet-Payrastre; Nicolas Loiseau; Hervé Guillou; Laïla Mselli-Lakhal. Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor. Scientific Reports 2019, 9, 1 -13.
AMA StyleCéline Lukowicz, Sandrine Ellero-Simatos, Marion Regnier, Fabiana Oliviero, Frédéric Lasserre, Arnaud Polizzi, Alexandra Montagner, Sarra Smati, Frédéric Boudou, Francoise Lenfant, Laurence Guzylack-Pirou, Sandrine Menard, Sharon Barretto, Anne Fougerat, Yannick Lippi, Claire Naylies, Justine Bertrand-Michel, Afifa Ait Belgnaoui, Vassilia Theodorou, Nicola Marchi, Pierre Gourdy, Laurence Gamet-Payrastre, Nicolas Loiseau, Hervé Guillou, Laïla Mselli-Lakhal. Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor. Scientific Reports. 2019; 9 (1):1-13.
Chicago/Turabian StyleCéline Lukowicz; Sandrine Ellero-Simatos; Marion Regnier; Fabiana Oliviero; Frédéric Lasserre; Arnaud Polizzi; Alexandra Montagner; Sarra Smati; Frédéric Boudou; Francoise Lenfant; Laurence Guzylack-Pirou; Sandrine Menard; Sharon Barretto; Anne Fougerat; Yannick Lippi; Claire Naylies; Justine Bertrand-Michel; Afifa Ait Belgnaoui; Vassilia Theodorou; Nicola Marchi; Pierre Gourdy; Laurence Gamet-Payrastre; Nicolas Loiseau; Hervé Guillou; Laïla Mselli-Lakhal. 2019. "Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor." Scientific Reports 9, no. 1: 1-13.
Fumonisins (FBs) are mycotoxins produced by Fusarium species that can contaminate human food and animal feed. Due to the harmful effects of FBs on animals, the European Union (EU) defined a recommendation of a maximum of 5 mg FBs (B1 + B2)/kg for complete feed for swine and 1 µg FBs/kg body weight per day as the tolerable daily intake for humans. The aim of this study was to evaluate the toxicity of dietary exposure to low doses of FBs, including a dose below the EU regulatory limits. Four groups of 24 weaned castrated male piglets were exposed to feed containing 0, 3.7, 8.1, and 12.2 mg/kg of FBs for 28 days; the impact was measured by biochemical analysis and histopathological observations. Dietary exposure to FBs at a low dose (3.7 mg/kg of feed) significantly increased the plasma sphinganine-to-sphingosine ratio. FBs-contaminated diets led to histological modifications in the intestine, heart, lung, lymphoid organs, kidney, and liver. The histological alterations in the heart and the intestine appeared at the lowest dose of FBs-contaminated diet (3.7 mg/kg feed) and in the kidney at the intermediate dose (8.1 mg/kg feed). At the highest dose tested (12.2 mg/kg feed), all the organs displayed histological alterations. This dose also induced biochemical modifications indicative of kidney and liver alterations. In conclusion, our data indicate that FBs-contaminated diets at doses below the EU regulatory limit cause histological lesions in several organs. This study suggests that EU recommendations for the concentration of FBs in animal feed, especially for swine, are not sufficiently protective and that regulatory doses should be modified for better protection of animal health.
Chloé Terciolo; Ana Paula Bracarense; Pollyana C.M.C. Souto; Anne-Marie Cossalter; Léonie Dopavogui; Nicolas Loiseau; Carlos A. F. Oliveira; Philippe Pinton; Isabelle P. Oswald. Fumonisins at Doses below EU Regulatory Limits Induce Histological Alterations in Piglets. Toxins 2019, 11, 548 .
AMA StyleChloé Terciolo, Ana Paula Bracarense, Pollyana C.M.C. Souto, Anne-Marie Cossalter, Léonie Dopavogui, Nicolas Loiseau, Carlos A. F. Oliveira, Philippe Pinton, Isabelle P. Oswald. Fumonisins at Doses below EU Regulatory Limits Induce Histological Alterations in Piglets. Toxins. 2019; 11 (9):548.
Chicago/Turabian StyleChloé Terciolo; Ana Paula Bracarense; Pollyana C.M.C. Souto; Anne-Marie Cossalter; Léonie Dopavogui; Nicolas Loiseau; Carlos A. F. Oliveira; Philippe Pinton; Isabelle P. Oswald. 2019. "Fumonisins at Doses below EU Regulatory Limits Induce Histological Alterations in Piglets." Toxins 11, no. 9: 548.
The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes, mostly xenobiotic-metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which was the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.
Sharon Ann Barretto; Frédéric Lasserre; Lorraine Smith; Tiffany Fougeray; Céline Lukowicz; Arnaud Polizzi; Sarra Smati; Marion Regnier; Claire Naylies; Colette Bétoulières; Yannick Lippi; Hervé Guillou; Nicolas Loiseau; Laurence Gamet-Payrastre; Laila Mselli-Lakhal; Sandrine Ellero-Simatos; Anne Fougerat. Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. International Journal of Molecular Sciences 2019, 20, 3767 .
AMA StyleSharon Ann Barretto, Frédéric Lasserre, Lorraine Smith, Tiffany Fougeray, Céline Lukowicz, Arnaud Polizzi, Sarra Smati, Marion Regnier, Claire Naylies, Colette Bétoulières, Yannick Lippi, Hervé Guillou, Nicolas Loiseau, Laurence Gamet-Payrastre, Laila Mselli-Lakhal, Sandrine Ellero-Simatos, Anne Fougerat. Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. International Journal of Molecular Sciences. 2019; 20 (15):3767.
Chicago/Turabian StyleSharon Ann Barretto; Frédéric Lasserre; Lorraine Smith; Tiffany Fougeray; Céline Lukowicz; Arnaud Polizzi; Sarra Smati; Marion Regnier; Claire Naylies; Colette Bétoulières; Yannick Lippi; Hervé Guillou; Nicolas Loiseau; Laurence Gamet-Payrastre; Laila Mselli-Lakhal; Sandrine Ellero-Simatos; Anne Fougerat. 2019. "Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice." International Journal of Molecular Sciences 20, no. 15: 3767.
The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes mostly xenobiotic metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.
Sharon Ann Barretto; Frederic Lasserre; Anne Fougerat; Lorraine Smith; Tiffany Fougeray; Celine Lukowicz; Arnaud Polizzi; Sarra Smati; Marion Régnier; Claire Naylies; Colette Betoulieres; Yannick Lippi; Hervé Guillou; Nicolas Loiseau; Laurence Payrastre; Laila Lakhal; Sandrine Ellero-Simatos; Anne Fougerat. Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. 2019, 1 .
AMA StyleSharon Ann Barretto, Frederic Lasserre, Anne Fougerat, Lorraine Smith, Tiffany Fougeray, Celine Lukowicz, Arnaud Polizzi, Sarra Smati, Marion Régnier, Claire Naylies, Colette Betoulieres, Yannick Lippi, Hervé Guillou, Nicolas Loiseau, Laurence Payrastre, Laila Lakhal, Sandrine Ellero-Simatos, Anne Fougerat. Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice. . 2019; ():1.
Chicago/Turabian StyleSharon Ann Barretto; Frederic Lasserre; Anne Fougerat; Lorraine Smith; Tiffany Fougeray; Celine Lukowicz; Arnaud Polizzi; Sarra Smati; Marion Régnier; Claire Naylies; Colette Betoulieres; Yannick Lippi; Hervé Guillou; Nicolas Loiseau; Laurence Payrastre; Laila Lakhal; Sandrine Ellero-Simatos; Anne Fougerat. 2019. "Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice." , no. : 1.
ObjectivesPeroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis.Methods/ResultsWe have investigated the role of hepatocyte PPARα in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Pparα-/-) mice and in mice lacking Pparα in hepatocyte (Pparαhep-/-). We provide evidence that Pparα deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD.ConclusionTaken together, our data support hepatocyte PPARα as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.HighlightsPparα deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesityHepatocyte-specific deletion of Pparα dissociates NAFLD from glucose intolerance in HFD-induced obesity obesityExtrahepatic PPARα activity contributes to the metabolic response to HFD-induced obesity
Marion Regnier; Arnaud Polizzi; Sarra Smati; Celine Lukowicz; Anne Fougerat; Yannick Lippi; Edwin Fouche; Frederic Lasserre; Claire Naylies; Colette Betoulieres; Valentin Barquissau; Etienne Mouisel; Justine Bertrand-Michel; Aurelie Batut; Talal Al Saati; Cecile Canlet; Marie Tremblay-Franco; Sandrine Ellero-Simatos; Minique Langin; Catherine Postic; Walter Wahli; Nicolas Loiseau; Herve Guillou; Alexandra Montagner. Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity. 2018, 488031 .
AMA StyleMarion Regnier, Arnaud Polizzi, Sarra Smati, Celine Lukowicz, Anne Fougerat, Yannick Lippi, Edwin Fouche, Frederic Lasserre, Claire Naylies, Colette Betoulieres, Valentin Barquissau, Etienne Mouisel, Justine Bertrand-Michel, Aurelie Batut, Talal Al Saati, Cecile Canlet, Marie Tremblay-Franco, Sandrine Ellero-Simatos, Minique Langin, Catherine Postic, Walter Wahli, Nicolas Loiseau, Herve Guillou, Alexandra Montagner. Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity. . 2018; ():488031.
Chicago/Turabian StyleMarion Regnier; Arnaud Polizzi; Sarra Smati; Celine Lukowicz; Anne Fougerat; Yannick Lippi; Edwin Fouche; Frederic Lasserre; Claire Naylies; Colette Betoulieres; Valentin Barquissau; Etienne Mouisel; Justine Bertrand-Michel; Aurelie Batut; Talal Al Saati; Cecile Canlet; Marie Tremblay-Franco; Sandrine Ellero-Simatos; Minique Langin; Catherine Postic; Walter Wahli; Nicolas Loiseau; Herve Guillou; Alexandra Montagner. 2018. "Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity." , no. : 488031.
Fumonisin B1 (FB1), a congener of fumonisins produced by Fusarium species, is the most abundant and most toxicologically active fumonisin. FB1 causes severe mycotoxicosis in animals, including nephrotoxicity, hepatotoxicity, and disruption of the intestinal barrier. However, mechanisms associated with FB1 toxicity are still unclear. Preliminary studies have highlighted the role of liver X receptors (LXRs) during FB1 exposure. LXRs belong to the nuclear receptor family and control the expression of genes involved in cholesterol and lipid homeostasis. In this context, the toxicity of FB1 was compared in female wild-type (LXR+/+) and LXRα,β double knockout (LXR−/−) mice in the absence or presence of FB1 (10 mg/kg body weight/day) for 28 days. Exposure to FB1 supplemented in the mice’s drinking water resulted in more pronounced hepatotoxicity in LXR−/− mice compared to LXR+/+ mice, as indicated by hepatic transaminase levels (ALT, AST) and hepatic inflammatory and fibrotic lesions. Next, the effect of FB1 exposure on the liver transcriptome was investigated. FB1 exposure led to a specific transcriptional response in LXR−/− mice that included altered cholesterol and bile acid homeostasis. ELISA showed that these effects were associated with an elevated FB1 concentration in the plasma of LXR−/− mice, suggesting that LXRs participate in intestinal absorption and/or clearance of the toxin. In summary, this study demonstrates an important role of LXRs in protecting the liver against FB1-induced toxicity, suggesting an alternative mechanism not related to the inhibition of sphingolipid synthesis for mycotoxin toxicity.
Marion Régnier; Arnaud Polizzi; Céline Lukowicz; Sarra Smati; Frédéric Lasserre; Yannick Lippi; Claire Naylies; Joelle Laffitte; Colette Bétoulières; Alexandra Montagner; Simon Ducheix; Pascal Gourbeyre; Sandrine Ellero-Simatos; Sandrine Menard; Justine Bertrand-Michel; Talal Al Saati; Jean-Marc Lobaccaro; Hester M. Burger; Wentzel C. Gelderblom; Hervé Guillou; Isabelle P. Oswald; Nicolas Loiseau. The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity. Archives of Toxicology 2018, 93, 505 -517.
AMA StyleMarion Régnier, Arnaud Polizzi, Céline Lukowicz, Sarra Smati, Frédéric Lasserre, Yannick Lippi, Claire Naylies, Joelle Laffitte, Colette Bétoulières, Alexandra Montagner, Simon Ducheix, Pascal Gourbeyre, Sandrine Ellero-Simatos, Sandrine Menard, Justine Bertrand-Michel, Talal Al Saati, Jean-Marc Lobaccaro, Hester M. Burger, Wentzel C. Gelderblom, Hervé Guillou, Isabelle P. Oswald, Nicolas Loiseau. The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity. Archives of Toxicology. 2018; 93 (2):505-517.
Chicago/Turabian StyleMarion Régnier; Arnaud Polizzi; Céline Lukowicz; Sarra Smati; Frédéric Lasserre; Yannick Lippi; Claire Naylies; Joelle Laffitte; Colette Bétoulières; Alexandra Montagner; Simon Ducheix; Pascal Gourbeyre; Sandrine Ellero-Simatos; Sandrine Menard; Justine Bertrand-Michel; Talal Al Saati; Jean-Marc Lobaccaro; Hester M. Burger; Wentzel C. Gelderblom; Hervé Guillou; Isabelle P. Oswald; Nicolas Loiseau. 2018. "The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity." Archives of Toxicology 93, no. 2: 505-517.
The liver plays a central role in the regulation of fatty acid metabolism. Hepatocytes are highly sensitive to nutrients and hormones that drive extensive transcriptional responses. Nuclear hormone receptors are key transcription factors involved in this process. Among these factors, PPARα is a critical regulator of hepatic lipid catabolism during fasting. This study aimed to analyse the wide array of hepatic PPARα-dependent transcriptional responses during fasting. We compared gene expression in male mice with a hepatocyte specific deletion of PPARα and their wild-type littermates in the fed (ad libitum) and 24-h fasted states. Liver samples were acquired, and transcriptome and lipidome analyses were performed. Our data extended and confirmed the critical role of hepatocyte PPARα as a central for regulator of gene expression during starvation. Interestingly, we identified novel PPARα-sensitive genes, including Cxcl-10, Rab30, and Krt23. We also found that liver phospholipid remodelling was a novel fasting-sensitive pathway regulated by PPARα. These results may contribute to investigations on transcriptional control in hepatic physiology and underscore the clinical relevance of drugs that target PPARα in liver pathologies, such as non-alcoholic fatty liver disease.
Marion Régnier; Arnaud Polizzi; Yannick Lippi; Edwin Fouché; Géraldine Michel; Céline Lukowicz; Sarra Smati; Alain Marrot; Frédéric Lasserre; Claire Naylies; Aurélie Batut; Fanny Viars; Justine Bertrand-Michel; Catherine Postic; Nicolas Loiseau; Walter Wahli; Hervé Guillou; Alexandra Montagner. Insights into the role of hepatocyte PPARα activity in response to fasting. Molecular and Cellular Endocrinology 2018, 471, 75 -88.
AMA StyleMarion Régnier, Arnaud Polizzi, Yannick Lippi, Edwin Fouché, Géraldine Michel, Céline Lukowicz, Sarra Smati, Alain Marrot, Frédéric Lasserre, Claire Naylies, Aurélie Batut, Fanny Viars, Justine Bertrand-Michel, Catherine Postic, Nicolas Loiseau, Walter Wahli, Hervé Guillou, Alexandra Montagner. Insights into the role of hepatocyte PPARα activity in response to fasting. Molecular and Cellular Endocrinology. 2018; 471 ():75-88.
Chicago/Turabian StyleMarion Régnier; Arnaud Polizzi; Yannick Lippi; Edwin Fouché; Géraldine Michel; Céline Lukowicz; Sarra Smati; Alain Marrot; Frédéric Lasserre; Claire Naylies; Aurélie Batut; Fanny Viars; Justine Bertrand-Michel; Catherine Postic; Nicolas Loiseau; Walter Wahli; Hervé Guillou; Alexandra Montagner. 2018. "Insights into the role of hepatocyte PPARα activity in response to fasting." Molecular and Cellular Endocrinology 471, no. : 75-88.
Non-alcoholic fatty liver disease (NAFLD) involves a panel of pathologies starting with hepatic steatosis and continuing to irreversible and serious conditions like steatohepatitis (NASH) and hepatocarcinoma. NAFLD is multifactorial in origin and corresponds to abnormal fat deposition in liver. Even if triglycerides are mostly associated with these pathologies, other lipid moieties seem to be involved in the development and severity of NAFLD. That is the case with sphingolipids and more particularly ceramides. In this review, we explore the relationship between NAFLD and sphingolipid metabolism. After providing an analysis of complex sphingolipid metabolism, we focus on the potential involvement of sphingolipids in the different pathologies associated with NAFLD. An unbalanced ratio between ceramides and terminal metabolic products in the liver and plasma promotes weight gain, inflammation, and insulin resistance. In the etiology of NAFLD, some sphingolipid species such as ceramides may be potential biomarkers for NAFLD. We review the clinical relevance of sphingolipids in liver diseases.
Marion Régnier; Arnaud Polizzi; Hervé Guillou; Nicolas Loiseau. Sphingolipid metabolism in non-alcoholic fatty liver diseases. Biochimie 2018, 159, 9 -22.
AMA StyleMarion Régnier, Arnaud Polizzi, Hervé Guillou, Nicolas Loiseau. Sphingolipid metabolism in non-alcoholic fatty liver diseases. Biochimie. 2018; 159 ():9-22.
Chicago/Turabian StyleMarion Régnier; Arnaud Polizzi; Hervé Guillou; Nicolas Loiseau. 2018. "Sphingolipid metabolism in non-alcoholic fatty liver diseases." Biochimie 159, no. : 9-22.
Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium species. In mammals, this toxin causes widespread organ-specific damage; it promotes hepatotoxicity, is immunotoxic, alters intestinal functions etc. Despite its inhibitory effect on de novo ceramide synthesis, its molecular mechanism of action and toxicity is not totally elucidated. To explore the mechanism of FB1 toxicity, we analyzed the transcriptome and the kinome of two organs targeted by FB1: the liver and the jejunum. Pigs were fed for 4 weeks a control diet or a FB1-contaminated diet (10 mg/kg). As expected, FB1-exposed pigs gained less weight and displayed a higher sphinganine/sphingosine ratio. Comparison of the transcriptomes and the kinomes of treated versus control pigs showed striking differences. Among the disrupted pathways in liver and jejunum, we highlight Protein Kinase B (AKT) / Phosphatase and tensin homolog (PTEN) at the intersection of the FB1-modulated pathways. Most of the effects of FB1 are mediated by the regulation of ceramide level, which influences protein phosphatase 2 (PP2A) and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. This pathway might be a new target to counteract toxic effect of Fumonisin B1, which is one of the most spread food contaminant in the world.
Marion Régnier; Pascal Gourbeyre; Philippe Pinton; Scott Napper; Joëlle Laffite; Anne‐Marie Cossalter; Jean‐Denis Bailly; Yannick Lippi; Justine Bertrand‐Michel; Ana Paula F.R.L. Bracarense; Hervé Guillou; Nicolas Loiseau; Isabelle P. Oswald. Identification of Signaling Pathways Targeted by the Food Contaminant FB1: Transcriptome and Kinome Analysis of Samples from Pig Liver and Intestine. Molecular Nutrition & Food Research 2017, 61, 1 .
AMA StyleMarion Régnier, Pascal Gourbeyre, Philippe Pinton, Scott Napper, Joëlle Laffite, Anne‐Marie Cossalter, Jean‐Denis Bailly, Yannick Lippi, Justine Bertrand‐Michel, Ana Paula F.R.L. Bracarense, Hervé Guillou, Nicolas Loiseau, Isabelle P. Oswald. Identification of Signaling Pathways Targeted by the Food Contaminant FB1: Transcriptome and Kinome Analysis of Samples from Pig Liver and Intestine. Molecular Nutrition & Food Research. 2017; 61 (12):1.
Chicago/Turabian StyleMarion Régnier; Pascal Gourbeyre; Philippe Pinton; Scott Napper; Joëlle Laffite; Anne‐Marie Cossalter; Jean‐Denis Bailly; Yannick Lippi; Justine Bertrand‐Michel; Ana Paula F.R.L. Bracarense; Hervé Guillou; Nicolas Loiseau; Isabelle P. Oswald. 2017. "Identification of Signaling Pathways Targeted by the Food Contaminant FB1: Transcriptome and Kinome Analysis of Samples from Pig Liver and Intestine." Molecular Nutrition & Food Research 61, no. 12: 1.
Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and β Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver.
Simon Ducheix; Alexandra Montagner; Arnaud Polizzi; Frédéric Lasserre; Marion Regnier; Alice Marmugi; Fadila Benhamed; Justine Bertrand-Michel; Laila Mselli-Lakhal; Nicolas Loiseau; Pascal G. Martin; Jean-Marc Lobaccaro; Laurent Ferrier; Catherine Postic; Hervé Guillou. Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling. PLOS ONE 2017, 12, e0181393 .
AMA StyleSimon Ducheix, Alexandra Montagner, Arnaud Polizzi, Frédéric Lasserre, Marion Regnier, Alice Marmugi, Fadila Benhamed, Justine Bertrand-Michel, Laila Mselli-Lakhal, Nicolas Loiseau, Pascal G. Martin, Jean-Marc Lobaccaro, Laurent Ferrier, Catherine Postic, Hervé Guillou. Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling. PLOS ONE. 2017; 12 (7):e0181393.
Chicago/Turabian StyleSimon Ducheix; Alexandra Montagner; Arnaud Polizzi; Frédéric Lasserre; Marion Regnier; Alice Marmugi; Fadila Benhamed; Justine Bertrand-Michel; Laila Mselli-Lakhal; Nicolas Loiseau; Pascal G. Martin; Jean-Marc Lobaccaro; Laurent Ferrier; Catherine Postic; Hervé Guillou. 2017. "Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling." PLOS ONE 12, no. 7: e0181393.
The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα−/− male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand.
Arnaud Polizzi; Edwin Fouché; Simon Ducheix; Frédéric Lasserre; Alice P. Marmugi; Laila Mselli-Lakhal; Nicolas Loiseau; Walter Wahli; Hervé Guillou; Alexandra Montagner. Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids. International Journal of Molecular Sciences 2016, 17, 1624 .
AMA StyleArnaud Polizzi, Edwin Fouché, Simon Ducheix, Frédéric Lasserre, Alice P. Marmugi, Laila Mselli-Lakhal, Nicolas Loiseau, Walter Wahli, Hervé Guillou, Alexandra Montagner. Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids. International Journal of Molecular Sciences. 2016; 17 (10):1624.
Chicago/Turabian StyleArnaud Polizzi; Edwin Fouché; Simon Ducheix; Frédéric Lasserre; Alice P. Marmugi; Laila Mselli-Lakhal; Nicolas Loiseau; Walter Wahli; Hervé Guillou; Alexandra Montagner. 2016. "Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids." International Journal of Molecular Sciences 17, no. 10: 1624.
Mycotoxins are the most frequently occurring natural contaminants in human and animal diet. Among them, deoxynivalenol (DON), produced by Fusarium, is one of the most prevalent and thus represents an important health risk. Recent detection methods revealed new mycotoxins and new molecules derivated from the “native” mycotoxins. The main derivates of DON are the acetylated forms produced by the fungi (3- and 15-acetyl-DON), the biologically “modified” forms produced by the plant (deoxynivalenol-3-β-d-glucopyranoside), or after bacteria transformation (de-epoxy DON, 3-epi-DON and 3-keto-DON) as well as the chemically “modified” forms (norDON A-C and DON-sulfonates). High proportions of acetylated and modified forms of DON co-occur with DON, increasing the exposure and the health risk. DON and its acetylated and modified forms are rapidly absorbed following ingestion. At the molecular level, DON binds to the ribosome, induces a ribotoxic stress leading to the activation of MAP kinases, cellular cell-cycle arrest and apoptosis. The toxic effects of DON include emesis and anorexia, alteration of intestinal and immune functions, reduced absorption of the nutrients as well as increased susceptibility to infection and chronic diseases. In contrast to DON, very little information exists concerning the acetylated and modified forms; some can be converted back to DON, their ability to bind to the ribosome and to induce cellular effects varies according to the toxin. Except for the acetylated forms, their toxicity and impact on human and animal health are poorly documented.
Delphine Payros; Imourana Alassane-Kpembi; Alix Pierron; Nicolas Loiseau; Philippe Pinton; Isabelle P. Oswald. Toxicology of deoxynivalenol and its acetylated and modified forms. Archives of Toxicology 2016, 90, 2931 -2957.
AMA StyleDelphine Payros, Imourana Alassane-Kpembi, Alix Pierron, Nicolas Loiseau, Philippe Pinton, Isabelle P. Oswald. Toxicology of deoxynivalenol and its acetylated and modified forms. Archives of Toxicology. 2016; 90 (12):2931-2957.
Chicago/Turabian StyleDelphine Payros; Imourana Alassane-Kpembi; Alix Pierron; Nicolas Loiseau; Philippe Pinton; Isabelle P. Oswald. 2016. "Toxicology of deoxynivalenol and its acetylated and modified forms." Archives of Toxicology 90, no. 12: 2931-2957.
Bacteria are able to de-epoxidize or epimerize deoxynivalenol (DON), a mycotoxin, to deepoxy-deoxynivalenol (deepoxy-DON or DOM-1) or 3-epi-deoxynivalenol (3-epi-DON), respectively. Using different approaches, the intestinal toxicity of 3 molecules was compared and the molecular basis for the reduced toxicity investigated. In human intestinal epithelial cells, deepoxy-DON and 3-epi-DON were not cytotoxic, did not change the oxygen consumption or impair the barrier function. In intestinal explants, exposure for 4 hours to 10 μM DON induced intestinal lesions not seen in explants treated with deepoxy-DON and 3-epi-DON. A pan-genomic transcriptomic analysis was performed on intestinal explants. 747 probes, representing 323 genes, were differentially expressed, between DON-treated and control explants. By contrast, no differentially expressed genes were observed between control, deepoxy-DON and 3-epi-DON treated explants. Both DON and its biotransformation products were able to fit into the pockets of the A-site of the ribosome peptidyl transferase center. DON forms three hydrogen bonds with the A site and activates MAPKinases (mitogen-activated protein kinases). By contrast deepoxy-DON and 3-epi-DON only form two hydrogen bonds and do not activate MAPKinases. Our data demonstrate that bacterial de-epoxidation or epimerization of DON altered their interaction with the ribosome, leading to an absence of MAPKinase activation and a reduced toxicity.
Alix Pierron; Sabria Mimoun; Leticia S. Murate; Nicolas Loiseau; Yannick Lippi; Ana-Paula F. L. Bracarense; Gerd Schatzmayr; Jian Wei He; Ting Zhou; Wulf-Dieter Moll; Isabelle P. Oswald. Microbial biotransformation of DON: molecular basis for reduced toxicity. Scientific Reports 2016, 6, 29105 .
AMA StyleAlix Pierron, Sabria Mimoun, Leticia S. Murate, Nicolas Loiseau, Yannick Lippi, Ana-Paula F. L. Bracarense, Gerd Schatzmayr, Jian Wei He, Ting Zhou, Wulf-Dieter Moll, Isabelle P. Oswald. Microbial biotransformation of DON: molecular basis for reduced toxicity. Scientific Reports. 2016; 6 (1):29105.
Chicago/Turabian StyleAlix Pierron; Sabria Mimoun; Leticia S. Murate; Nicolas Loiseau; Yannick Lippi; Ana-Paula F. L. Bracarense; Gerd Schatzmayr; Jian Wei He; Ting Zhou; Wulf-Dieter Moll; Isabelle P. Oswald. 2016. "Microbial biotransformation of DON: molecular basis for reduced toxicity." Scientific Reports 6, no. 1: 29105.
Objective Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD). Design We constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing. Results Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing. Conclusions Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.
Alexandra Montagner; Arnaud Polizzi; Edwin Fouché; Simon Ducheix; Yannick Lippi; Frédéric Lasserre; Valentin Barquissau; Marion Regnier; Céline Lukowicz; Fadila Benhamed; Alison Iroz; Justine Bertrand-Michel; Talal Al Saati; Patricia Cano; Laila Mselli-Lakhal; Gilles Mithieux; Fabienne Rajas; Sandrine Lagarrigue; Thierry Pineau; Nicolas Loiseau; Catherine Postic; Dominique Langin; Walter Wahli; Hervé Guillou. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 2016, 65, 1202 -1214.
AMA StyleAlexandra Montagner, Arnaud Polizzi, Edwin Fouché, Simon Ducheix, Yannick Lippi, Frédéric Lasserre, Valentin Barquissau, Marion Regnier, Céline Lukowicz, Fadila Benhamed, Alison Iroz, Justine Bertrand-Michel, Talal Al Saati, Patricia Cano, Laila Mselli-Lakhal, Gilles Mithieux, Fabienne Rajas, Sandrine Lagarrigue, Thierry Pineau, Nicolas Loiseau, Catherine Postic, Dominique Langin, Walter Wahli, Hervé Guillou. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut. 2016; 65 (7):1202-1214.
Chicago/Turabian StyleAlexandra Montagner; Arnaud Polizzi; Edwin Fouché; Simon Ducheix; Yannick Lippi; Frédéric Lasserre; Valentin Barquissau; Marion Regnier; Céline Lukowicz; Fadila Benhamed; Alison Iroz; Justine Bertrand-Michel; Talal Al Saati; Patricia Cano; Laila Mselli-Lakhal; Gilles Mithieux; Fabienne Rajas; Sandrine Lagarrigue; Thierry Pineau; Nicolas Loiseau; Catherine Postic; Dominique Langin; Walter Wahli; Hervé Guillou. 2016. "Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD." Gut 65, no. 7: 1202-1214.
Natural food contaminants such as mycotoxins are an important problem for human health. Deoxynivalenol (DON) is one of the most common mycotoxins detected in cereals and grains. Its toxicological effects mainly concern the immune system and the gastrointestinal tract. This toxin is a potent ribotoxic stressor leading to MAP kinase activation and inflammatory response. DON frequently co-occurs with its glucosylated form, the masked mycotoxin deoxynivalenol-3-β-d-glucoside (D3G). The toxicity of this later compound remains unknown in mammals. This study aimed to assess the ability of D3G to elicit a ribotoxic stress and to induce intestinal toxicity. The toxicity of D3G and DON (0–10 µM) was studied in vitro, on the human intestinal Caco-2 cell line, and ex vivo, on porcine jejunal explants. First, an in silico analysis revealed that D3G, contrary to DON, was unable to bind to the A-site of the ribosome peptidyl transferase center, the main targets for DON toxicity. Accordingly, D3G did not activate JNK and P38 MAPKs in treated Caco-2 cells and did not alter viability and barrier function on cells, as measured by the trans-epithelial electrical resistance. Treatment of intestinal explants for 4 h with 10 µM DON induced morphological lesions and up-regulated the expression of pro-inflammatory cytokines as measured by qPCR and pan-genomic microarray analysis. By contrast, expression profile of D3G-treated explants was similar to that of controls, and these explants did not show histomorphology alteration. In conclusion, our data demonstrated that glucosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity.
Alix Pierron; Sabria Mimoun; Leticia Sayuri Murate; Nicolas Loiseau; Yannick Lippi; Ana-Paula F. L. Bracarense; Laurence Liaubet; Gerd Schatzmayr; Franz Berthiller; Wulf-Dieter Moll; Isabelle P. Oswald. Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside. Archives of Toxicology 2015, 90, 2037 -2046.
AMA StyleAlix Pierron, Sabria Mimoun, Leticia Sayuri Murate, Nicolas Loiseau, Yannick Lippi, Ana-Paula F. L. Bracarense, Laurence Liaubet, Gerd Schatzmayr, Franz Berthiller, Wulf-Dieter Moll, Isabelle P. Oswald. Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside. Archives of Toxicology. 2015; 90 (8):2037-2046.
Chicago/Turabian StyleAlix Pierron; Sabria Mimoun; Leticia Sayuri Murate; Nicolas Loiseau; Yannick Lippi; Ana-Paula F. L. Bracarense; Laurence Liaubet; Gerd Schatzmayr; Franz Berthiller; Wulf-Dieter Moll; Isabelle P. Oswald. 2015. "Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside." Archives of Toxicology 90, no. 8: 2037-2046.