title: Sox17 regulates liver lipid metabolism and adaptation to fasting.
abstract: Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rommelaere
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Millet
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Thien-Phong
authors.initials: TP
authors.lastname: Vu Manh
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gensollen
authors.affiliation: Université de Bourgogne, Laboratoire BioPeroxIL, EA7270, Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Andreoletti
authors.affiliation: Université de Bourgogne, Laboratoire BioPeroxIL, EA7270, Dijon, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Cherkaoui-Malki
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bourges
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Escalière
authors.affiliation: University of Texas Southwestern Medical Center, Center for Genetics of Host Defense, Dallas, Texas, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: University of Texas Southwestern Medical Center, Center for Genetics of Host Defense, Dallas, Texas, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Aix-Marseille University, UMR_S 1090, TGML/TAGC, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Imbert
authors.affiliation: University of Texas Southwestern Medical Center, Center for Genetics of Host Defense, Dallas, Texas, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Veterinary Anatomy, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoshiakira
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Malissen
authors.affiliation: Institut Pasteur de Lille, INSERM U1011, Université de Lille 2, EGID, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.affiliation: Institut Pasteur de Lille, INSERM U1011, Université de Lille 2, EGID, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Galland
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000581:Amidohydrolases / Q000097:blood / Q000378:metabolism; D000818:Animals; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000097:blood / Q000378:metabolism; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D058851:GPI-Linked Proteins; D024002:HMGB Proteins; D047493:PPAR alpha; D055758:SOX9 Transcription Factor; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C527933:Sox9 protein, mouse; D000581:Amidohydrolases; C022314:pantetheinase