Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2.

Autor: Burdin DV; Department of Physiology, Saint Petersburg State University, 199034 Saint Petersburg, Russia., Kolobov AA; Department of Biochemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia., Brocker C; National Cancer Institute, NIH, Bethesda, MD, 20892, USA., Soshnev AA; The Rockefeller University, New York, NY, 10065, USA., Samusik N; Stanford University School of Medicine, Stanford, CA, 94305, USA., Demyanov AV; Institute of Highly Pure Biopreparations, 197110 Saint Petersburg, Russia., Brilloff S; University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany., Jarzebska N; University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany., Martens-Lobenhoffer J; Institute of Clinical Pharmacology, Otto-von-Guericke University, 39120 Magdeburg, Germany., Mieth M; Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Maas R; Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Bornstein SR; Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany., Bode-Böger SM; Institute of Clinical Pharmacology, Otto-von-Guericke University, 39120 Magdeburg, Germany., Gonzalez F; National Cancer Institute, NIH, Bethesda, MD, 20892, USA., Weiss N; University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany., Rodionov RN; University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2016 Oct 18; Vol. 6, pp. 35503. Date of Electronic Publication: 2016 Oct 18.
DOI: 10.1038/srep35503
Abstrakt: 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.
Databáze: MEDLINE
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