PUBLICATION

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

Authors
Wohlfart, D.P., Lou, B., Middel, C.S., Morgenstern, J., Fleming, T., Sticht, C., Hausser, I., Hell, R., Hammes, H.P., Szendrödi, J., Nawroth, P.P., Kroll, J.
ID
ZDB-PUB-220204-11
Date
2022
Source
Redox Biology   50: 102249 (Journal)
Registered Authors
Kroll, Jens
Keywords
Acetaldehyde (AA), Aldehyde dehydrogenase (ALDH), Glucose metabolism, Microvascular organ complications, Reactive carbonyl species (RCS), Zebrafish
Datasets
GEO:GSE189416
MeSH Terms
  • Aldehyde Dehydrogenase, Mitochondrial/genetics
  • Aldehyde Dehydrogenase, Mitochondrial/metabolism
  • Animals
  • Zebrafish*/metabolism
  • Aldehyde Dehydrogenase/genetics
  • Acetaldehyde*/metabolism
  • Glucose/metabolism
(all 7)
PubMed
35114580 Full text @ Redox Biol.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    zf3854
      		Small Deletion
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      aldh2.1CRISPR2-aldh2.1,aldh2.2CRISPR
      aldh2.2CRISPR2-aldh2.1,aldh2.2CRISPR
      1 - 2 of 2
      Show
      Fish
      No data available
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
      No data available
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      Citation
      Wohlfart, D.P., Lou, B., Middel, C.S., Morgenstern, J., Fleming, T., Sticht, C., Hausser, I., Hell, R., Hammes, H.P., Szendrödi, J., Nawroth, P.P., Kroll, J. (2022) Accumulation of acetaldehyde in aldh2.1-/- zebrafish causes increased retinal angiogenesis and impaired glucose metabolism. Redox Biology. 50:102249.