6533b853fe1ef96bd12ac0ad
RESEARCH PRODUCT
Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors.
Insook KimRinke StienstraPascal EscherFrank J. GonzalezSander KerstenWalter WahliNguan Soon TanStéphane MandardBéatrice DesvergneMichael Müllersubject
Animals; Chromatin/ultrastructure; DNA Primers; Gene Expression Regulation Enzymologic; Glycogen Synthase/genetics; Hepatocytes/enzymology; Hepatocytes/physiology; Mice; Mice Knockout; Peroxisome Proliferator-Activated Receptors/deficiency; Peroxisome Proliferator-Activated Receptors/genetics; Polymerase Chain Reaction; RNA/genetics; RNA/isolation & purification; Rats; Transcription GeneticTranscription GeneticPeroxisome proliferator-activated receptorMESH : HepatocytesPPREPolymerase Chain Reactionadipose-tissuePPARMESH: HepatocytesMice0302 clinical medicineMESH: Animals610 Medicine & healthchemistry.chemical_classificationRegulation of gene expression0303 health sciencesGlycogenglycogen-synthaseChromatinGlycogen Synthase030220 oncology & carcinogenesisMESH : DNA PrimersmicroarrayMESH: DNA Primersmedicine.medical_specialtyHealth aging / healthy living [IGMD 5]fatty-acid oxidationliverGene Expression Regulation EnzymologicMESH: Chromatin03 medical and health sciencesskeletal-muscleGlycogen synthaseMolecular Biology[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular BiologyHNF4αVLAGPharmacologybeta/deltaMESH: Polymerase Chain Reactionresponse elementsMESH : Peroxisome Proliferator-Activated ReceptorsEndocrinologychemistryMicrobial pathogenesis and host defense [UMCN 4.1]Response elementPeroxisome Proliferator-Activated ReceptorsAdipose tissueMESH: Peroxisome Proliferator-Activated Receptorsin-vivoMESH: Mice KnockoutTransactivationchemistry.chemical_compoundVoeding Metabolisme en GenomicaMESH : RNAMESH : Polymerase Chain ReactionMice KnockoutMESH : ChromatinMESH : RatsMESH: Gene Expression Regulation EnzymologicMetabolism and Genomicsadipose tissueMetabolisme en GenomicaMolecular MedicineNutrition Metabolism and GenomicsMESH : Glycogen SynthaseResearch ArticleMESH: Ratsglycogen synthase 2610 Medicine & healthBiologyMESH : Gene Expression Regulation EnzymologicCellular and Molecular NeuroscienceVoedingMESH: RNAInternal medicineMESH : MicemedicineAnimals[SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular BiologyTranscription factorMESH: Micealpha ppar-alpha030304 developmental biologyNutritionDNA PrimersMESH: Glycogen SynthaseMESH: Transcription GeneticMESH : Transcription GeneticCell BiologyRatsgene transcriptionbiology.proteinHepatocytesRNAMESH : Mice KnockoutgammaMESH : Animalsmetabolismdescription
International audience; Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARalpha, PPARbeta/delta and PPARgamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPARalpha-/-, PPARbeta/delta-/- and PPARgamma+/- mice. Furthermore, synthetic PPARbeta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARalpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4alpha). In adipose tissue, which does not express HNF4alpha, DR-1prom is occupied by PPARbeta/delta and PPARgamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4alpha is mediated by two distinct response elements.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2007-05-01 |