Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors.
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.
Mandard
S
S
Nutrition, Metabolism and Genomics group and Nutrigenomics Consortium, Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV, Wageningen, The Netherlands.
Stienstra
R
R
Escher
P
P
Tan
N S
NS
Kim
I
I
Gonzalez
F J
FJ
Wahli
W
W
Desvergne
B
B
Müller
M
M
Kersten
S
S
D000818:Animals; D002843:Chromatin / Q000648:ultrastructure; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D006006:Glycogen Synthase / Q000235:genetics*; D022781:Hepatocytes / Q000201:enzymology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D047492:Peroxisome Proliferator-Activated Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D014158:Transcription, Genetic
D002843:Chromatin; D017931:DNA Primers; D047492:Peroxisome Proliferator-Activated Receptors; D012313:RNA; D006006:Glycogen Synthase