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

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 glucos...

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Published in:Cellular and molecular life sciences : CMLS 2007-05, Vol.64 (9), p.1145-57
Main Authors: Mandard, Stéphane, Stienstra, Rinke, Escher, Pascal, Tan, Nguan Soon, Kim, Insook, Gonzalez, Frank J., Wahli, Walter, Desvergne, Béatrice, Müller, Michael, Kersten, Sander
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Chromatin
DNA Primers
Gene Expression Regulation, Enzymologic
Glycogen Synthase
Hepatocytes
Life Sciences
Mice
Mice, Knockout
Peroxisome Proliferator-Activated Receptors
Polymerase Chain Reaction
Rats
RNA
Transcription, Genetic
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Summary: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.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-007-7006-1