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Accumulation of acetaldehyde in aldh2.1-/- zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-...

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Hauptverfasser: Wohlfart, David Philipp (VerfasserIn) , Lou, Bowen (VerfasserIn) , Heim, Chiara (VerfasserIn) , Morgenstern, Jakob (VerfasserIn) , Fleming, Thomas (VerfasserIn) , Sticht, Carsten (VerfasserIn) , Haußer-Siller, Ingrid (VerfasserIn) , Hell, Rüdiger (VerfasserIn) , Hammes, Hans-Peter (VerfasserIn) , Szendrödi, Julia (VerfasserIn) , Nawroth, Peter Paul (VerfasserIn) , Kroll, Jens (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 26 January 2022
In: Redox Biology
Year: 2022, Jahrgang: 50, Pages: 1-15
ISSN:2213-2317
DOI:10.1016/j.redox.2022.102249
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.redox.2022.102249
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2213231722000210
Volltext
Verfasserangaben:David Philipp Wohlfart, Bowen Lou, Chiara Simone Middel, Jakob Morgenstern, Thomas Fleming, Carsten Sticht, Ingrid Hausser, Rüdiger Hell, Hans-Peter Hammes, Julia Szendrödi, Peter Paul Nawroth, Jens Kroll
Beschreibung
Zusammenfassung:Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1−/− animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1−/− zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1−/− zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase (gck) and glucose-6-phosphatase (g6pc), which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.
Beschreibung:Im Titel ist "-/-" hochgestellt
Gesehen am 01.06.2022
Beschreibung:Online Resource
ISSN:2213-2317
DOI:10.1016/j.redox.2022.102249

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