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Neuschäfer-Rube, Frank ; Lieske, Stefanie ; Kuna, Manuela ; Henkel, Janin ; Perry, Rachel J. ; Erion, Derek M. ; Pesta, Dominik ; Willmes, Diana M. ; Brachs, Sebastian ; von Loeffelholz, Christian ; Tolkachov, Alexander ; Schupp, Michael ; Pathe-Neuschäfer-Rube, Andrea ; Pfeiffer, Andreas F. H. ; Shulman, Gerald I. ; Püschel, Gerhard P. ; Birkenfeld, Andreas L.:
The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes.
In: Diabetes.
Bd. 63
(2014)
Heft 3
.
- S. 1048-1057.
ISSN 1939-327X
DOI: https://doi.org/10.2337/db13-0749
Abstract
Reduced expression of the INDY (I'm not dead yet) tricarboxylate carrier increased the life span in different species by mechanisms akin to caloric restriction. Mammalian INDY homolog (mIndy, SLC13A5) gene expression seems to be regulated by hormonal and/or nutritional factors. The underlying mechanisms are still unknown. The current study revealed that mIndy expression and [(14)C]-citrate uptake was induced by physiological concentrations of glucagon via a cAMP-dependent and cAMP-responsive element-binding protein (CREB)-dependent mechanism in primary rat hepatocytes. The promoter sequence of mIndy located upstream of the most frequent transcription start site was determined by 5'-rapid amplification of cDNA ends. In silico analysis identified a CREB-binding site within this promoter fragment of mIndy. Functional relevance for the CREB-binding site was demonstrated with reporter gene constructs that were induced by CREB activation when under the control of a fragment of a wild-type promoter, whereas promoter activity was lost after site-directed mutagenesis of the CREB-binding site. Moreover, CREB binding to this promoter element was confirmed by chromatin immunoprecipitation in rat liver. In vivo studies revealed that mIndy was induced in livers of fasted as well as in high-fat-diet-streptozotocin diabetic rats, in which CREB is constitutively activated. mIndy induction was completely prevented when CREB was depleted in these rats by antisense oligonucleotides. Together, these data suggest that mIndy is a CREB-dependent glucagon target gene that is induced in fasting and in type 2 diabetes. Increased mIndy expression might contribute to the metabolic consequences of diabetes in the liver.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten > Fakultät für Lebenswissenschaften: Lebensmittel, Ernährung und Gesundheit Fakultäten Fakultäten > Fakultät für Lebenswissenschaften: Lebensmittel, Ernährung und Gesundheit > Lehrstuhl Biochemie der Ernährung > Lehrstuhl Biochemie der Ernährung - Univ.-Prof. Dr. Janin Henkel-Oberländer Fakultäten > Fakultät für Lebenswissenschaften: Lebensmittel, Ernährung und Gesundheit > Lehrstuhl Biochemie der Ernährung |
| Titel an der UBT entstanden: | Nein |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| Eingestellt am: | 26 Apr 2021 11:55 |
| Letzte Änderung: | 19 Okt 2022 12:53 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/64435 |