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Burdin, Dmitry V.; Kolobov, Alexey A.; Brocker, Chad; Soshnev, Alexey A.; Samusik, Nikolay; Demyanov, Anton V.; Brilloff, Silke; Jarzebska, Natalia; Martens-Lobenhoffer, Jens; Mieth, Maren; Maas, Renke; Bornstein, Stefan R.; Bode-Böger, Stefanie M.; Gonzalez, Frank; Weiss, Norbert; Rodionov, Roman N.

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

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  • Medientyp: E-Artikel
  • Titel: Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2
  • Beteiligte: Burdin, Dmitry V.; Kolobov, Alexey A.; Brocker, Chad; Soshnev, Alexey A.; Samusik, Nikolay; Demyanov, Anton V.; Brilloff, Silke; Jarzebska, Natalia; Martens-Lobenhoffer, Jens; Mieth, Maren; Maas, Renke; Bornstein, Stefan R.; Bode-Böger, Stefanie M.; Gonzalez, Frank; Weiss, Norbert; Rodionov, Roman N.
  • Erschienen: Springer Science and Business Media LLC, 2016
  • Erschienen in: Scientific Reports
  • Sprache: Englisch
  • DOI: 10.1038/srep35503
  • ISSN: 2045-2322
  • Schlagwörter: Multidisciplinary
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>AGXT2</jats:italic> promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of <jats:italic>Agxt2</jats:italic> core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to <jats:italic>Agxt2</jats:italic> promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of <jats:italic>Hnf4a</jats:italic> led to an almost 50% reduction in <jats:italic>Agxt2</jats:italic> mRNA levels in Hepa 1–6 cells. Liver-specific <jats:italic>Hnf4a</jats:italic> knockout mice exhibited a 90% decrease in liver <jats:italic>Agxt2</jats:italic> 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 <jats:italic>Agxt2</jats:italic> expression. Considering a strong association between human <jats:italic>HNF4A</jats:italic> 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.</jats:p>
  • Zugangsstatus: Freier Zugang