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

Cell Mol Life Sci. 2007 May;64(9):1145-57. doi: 10.1007/s00018-007-7006-1.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Peroxisome Proliferator-Activated Receptors / physiology*
  • Polymerase Chain Reaction
  • RNA / genetics
  • RNA / isolation & purification
  • Rats
  • Transcription, Genetic

Substances

  • Chromatin
  • DNA Primers
  • Peroxisome Proliferator-Activated Receptors
  • RNA
  • Glycogen Synthase