- AutorIn
- Dmitry V. Burdin
- Alexey A. Kolobov
- Chad Brocker
- Alexey A. Soshnev
- Nikolay Samusik
- Anton v. Demyanov
- Silke Brilloff
- Natalia Jarzebska
- Jens Martens-Lobenhoffer
- Maren Mieth
- Renke Maas
- Prof. Dr. med. Stefan R. Bornstein
- Stefanie M. Bode-Böger
- Frank Gonzalez
- Prof. Dr. med. Norbert Weiss
- Dr. Roman N. Rodionov
- Titel
- Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2
- Zitierfähige Url:
- https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa-226882
- Quellenangabe
- Scientific Reports (2016), 7, ISSN: 2045-2322. DOI: 10.1038/srep35503. Artikelnr.: 35503.
- Erstveröffentlichung
- 2016
- Abstract (EN)
- Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1–6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.
- Andere Ausgabe
- DOI: 10.1038/srep35503
- Link zum Artikel, der zuerst in der Zeitschrift 'Scientific Reports' erschienen ist.
Link: http://dx.doi.org/10.1038/srep35503 - Freie Schlagwörter (DE)
- Kardiovaskuläre Genetik, Genregulation, Hypertonie Prognostische Marker Transkriptionselemente, Technische Universität Dresden, Publikationsfonds
- Freie Schlagwörter (EN)
- Cardiovascular genetics, Gene regulation, Hypertension, Technische Universität Dresden, Publishing Fund Prognostic markers, Transcriptional regulatory elements
- Verlag
- Nature Publishing Group, London
- URN Qucosa
- urn:nbn:de:bsz:14-qucosa-226882
- Veröffentlichungsdatum Qucosa
- 21.07.2017
- Dokumenttyp
- Artikel
- Sprache des Dokumentes
- Englisch
- Lizenz / Rechtehinweis
- CC BY 4.0