Research Article

Cellular and Molecular Life Sciences

, 64:1145

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors

  • S. MandardAffiliated withNutrition, Metabolism and Genomics group and Nutrigenomics Consortium, Division of Human Nutrition, Wageningen UniversityINSERM UMR 866 (Lipides, Nutrition et Cancer, équipe Biochimie Métabolique et Nutritionnelle), Faculté des Sciences Gabriel, Université de Bourgogne
  • , R. StienstraAffiliated withNutrition, Metabolism and Genomics group and Nutrigenomics Consortium, Division of Human Nutrition, Wageningen University
  • , P. EscherAffiliated withInstitute of Physiology, Pharmazentrum, University of Basel
  • , N. S. TanAffiliated withCenter for Integrative Genomics, Université de Lausanne
  • , I. KimAffiliated withLaboratory of Metabolism, Division of Basic Sciences, National Cancer Institute
  • , F. J. GonzalezAffiliated withLaboratory of Metabolism, Division of Basic Sciences, National Cancer Institute
  • , W. WahliAffiliated withCenter for Integrative Genomics, Université de Lausanne
  • , B. DesvergneAffiliated withCenter for Integrative Genomics, Université de Lausanne
  • , M. MüllerAffiliated withNutrition, Metabolism and Genomics group and Nutrigenomics Consortium, Division of Human Nutrition, Wageningen University
    • , S. KerstenAffiliated withNutrition, Metabolism and Genomics group and Nutrigenomics Consortium, Division of Human Nutrition, Wageningen University Email author 

Abstract.

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 PPARα, PPARβ/δ and PPARγ. Expression of Gys-2 is significantly reduced in adipose tissue of PPARα-/-, PPARβ/δ-/- and PPARγ+/- mice. Furthermore, synthetic PPARβ/δ, and γ agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARα 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 (HNF4α). In adipose tissue, which does not express HNF4α, DR-1prom is occupied by PPARβ/δ and PPARγ, 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 HNF4α is mediated by two distinct response elements.

Keywords.

PPAR HNF4α liver adipose tissue microarray glycogen synthase 2 gene transcription PPRE