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

Mandard, S; Stienstra, R; Escher, Pascal; Tan, N S; Kim, I; Gonzalez, F J; Wahli, W; Desvergne, B; Müller, M; Kersten, S (2007). Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors. Cellular and molecular life sciences, 64(9), pp. 1145-1157. Springer 10.1007/s00018-007-7006-1

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology

UniBE Contributor:

Escher, Pascal

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1420-682X

Publisher:

Springer

Language:

English

Submitter:

PD Dr. Pascal Escher

Date Deposited:

10 Jul 2017 16:00

Last Modified:

31 Jul 2017 08:31

Publisher DOI:

10.1007/s00018-007-7006-1

PubMed ID:

17437057

BORIS DOI:

10.7892/boris.101760

URI:

https://boris.unibe.ch/id/eprint/101760

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