Glucocorticoid receptor-PPAR alpha axis in fetal mouse liver prepares neonates for milk lipid catabolism
| Autor: | Eeswari Paramalingam, Chek Kun Tan, Nicolas Leuenberger, Alexandra Montagner, Nourhène Khaled, Justine Bertrand-Michel, Hervé Guillou, Walter Wahli, Gianpaolo Rando |
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| Přispěvatelé: | Center for Integrative Genomics, Université de Lausanne, Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Plateforme Metatoul, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherche 150 - Bio-Médicale de Toulouse, Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung, Nanyang Technological University, Bonizzi-Theler Stiftung, Human Frontier Science Program, 7th EU Program TORNADO, Pôle de Recherche National 'Frontiers in Genetics', Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Nanyang Technological University (NTU), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), ProdInra, Archive Ouverte, Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), MetaboHUB-MetaToul, Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Lee Kong Chian School of Medicine (LKCMedicine) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
FGF21 récepteur ppar Mouse [SDV]Life Sciences [q-bio] Peroxisome proliferator-activated receptor souris newborn animal PPARα 0302 clinical medicine Glucocorticoid receptor pparalpha glucocorticoid receptor catabolisme lipidique Biology (General) chemistry.chemical_classification General Neuroscience hepatic steatosis Gene Expression Regulation Developmental General Medicine foie ketone body [SDV] Life Sciences [q-bio] Milk Liver Medicine Energy source Research Article medicine.medical_specialty mice QH301-705.5 Science Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Receptors Glucocorticoid activation de la transcription Internal medicine medicine Animals PPAR alpha Epigenetics Fetus General Immunology and Microbiology Catabolism lipid catabolism HDAC3 nouveau né Lipid metabolism Lipid Metabolism 030104 developmental biology Endocrinology Developmental Biology and Stem Cells Metabolism chemistry liver function tests Energy Metabolism 030217 neurology & neurosurgery |
| Zdroj: | eLife eLife, eLife Sciences Publication, 2016, 5, 31 p. ⟨10.7554/eLife.11853⟩ Elife, vol. 5, pp. e28536 eLife, 2016, 5, 31 p. ⟨10.7554/eLife.11853⟩ eLife (5), 31 p.. (2016) eLife, Vol 5 (2016) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.11853⟩ |
| Popis: | In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPARα, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPARα axis in which GR directly regulates the transcriptional activation of PPARα by binding to its promoter. Certain PPARα target genes such as Fgf21 remain repressed in the fetal liver and become PPARα responsive after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPARα in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands. DOI: http://dx.doi.org/10.7554/eLife.11853.001 eLife digest Birth is a highly stressful and critical event. In the womb, babies rely on the supply of oxygen and nutrients provided by the placenta. However, once they are born they need to breathe for themselves and gain all their nutrients from suckling milk. The placenta provides a sugar-rich diet, while milk is richer in fat. Failing to cope with this change in diet leads to serious complications and sometimes death. Therefore, a better understanding of how the body adapts to these changes may shed light on pathways that are important for good health in later life. The liver plays a central role in processing the nutrients absorbed by the gut. It uses fats to produce molecules called ketone bodies, such as β-hydroxybutyrate, which are then used as fuel by other tissues and organs including the heart, muscle and the brain. A protein called PPARα controls the production of ketone bodies primarily by regulating genes that are involved in the uptake and breakdown of fat in the liver. However, little is known about how this protein affects the development of the liver. Here, Rando, Tan et al. report that mice start to produce more PPARα in the liver shortly before birth. This ultimately activates several genes that encode enzymes that break down fats. The experiments show that during labor, stress hormones called glucocorticoids directly stimulate the production of PPARα in the liver of the fetus to prepare newborn mice for harnessing energy from fat-rich milk. In the absence of PPARα, mouse liver cells are less able to break down fats after birth and so start to accumulate fat, resulting in fewer ketone bodies being produced. Rando, Tan et al. show that β-hydroxybutyrate regulates some PPARα target genes, including one called Fgf21. The activity of this gene increases only after milk suckling starts and it encodes a protein that enhances the breakdown of fats in the liver. Without PPARα, the expression levels of its target genes, including Fgf21, do not increase after birth, which promotes the build up of fats in liver cells, a condition known as liver steatosis. Overall, the results reported by Rando, Tan et al. highlight how stress during labor plays an important role in priming the body to cope with a fat-rich diet after birth. Future studies will need to determine if stress hormones and ketone bodies could be used as therapies for babies born by caesarean section with liver steatosis. DOI: http://dx.doi.org/10.7554/eLife.11853.002 |
| Databáze: | OpenAIRE |
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