title: The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice.
abstract: Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARα. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII-DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARα target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Julien
authors.initials: J
authors.lastname: Planchais
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fauveau
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and Laboratoires Fabre, Boulogne Cedex, France.
authors.forename: Lou Dan
authors.initials: LD
authors.lastname: Qing
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Lina
authors.initials: L
authors.lastname: Sabra-Makke
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bossard
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vasseur-Cognet
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and jean-paul.pegorier@univ-paris-diderot.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pégorier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051837:COUP Transcription Factor II / Q000502:physiology*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics; D011247:Pregnancy
chemical_list: D051837:COUP Transcription Factor II; D005227:Fatty Acids; C497587:Nr2f2 protein, mouse; D047493:PPAR alpha
keywords: chicken ovalbumin upstream promoter transcription factor ii inactivation; fatty acid oxidation; gluconeogenesis; nuclear receptors; postnatal liver metabolism