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Lou, B.* ; Boger, M.* ; Bennewitz, K.* ; Sticht, C.* ; Kopf, S.* ; Morgenstern, J. ; Fleming, T.* ; Hell, R.* ; Yuan, Z.* ; Nawroth, P.P. ; Kroll, J.*

Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans.

Redox Biol. 37:101723 (2020)

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	Open Access Gold

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Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1(-/-) zebrafish mutants were generated using CRISPR-Cas9. Vasculature and pancreas morphology were analysed by zebrafish transgenic reporter lines. Corresponding reactive carbonyl species (RCS), glucose, transcriptome and metabolomics screenings were performed and ALDH activity was measured for further verification. Aldh3a1(-/-) zebrafish larvae displayed retinal vasodilatory alterations, impaired glucose homeostasis, which can be aggravated via pdx1 silencing induced hyperglycaemia. Unexpectedly, MG was not altered, but 4-hydroxynonenal (4-HNE), another prominent lipid peroxidation RCS exhibited high affinity with Aldh3a1, was increased in aldh3a1 mutants. 4-HNE was responsible for the retinal phenotype via pancreas disruption induced hyperglycaemia and can be rescued via L-Carnosine treatment. Furthermore, in type 2 diabetic patients, serum 4-HNE was increased and correlated with disease progression. Thus, our data suggest impaired 4-HNE detoxification and elevated 4-HNE concentration as biomarkers but also the possible inducers for diabetes, from genetic susceptibility to the pathological progression.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Aldh3a1 ; Reactive Carbonyl Species ; 4-hydroxynonenal ; Glucose Homeostasis ; Diabetes; Lipid-peroxidation; Aldehyde Dehydrogenase; Ppar-delta; In-vivo; Methylglyoxal; Expression; Damage; Activation; Metformin; Protects

ISSN (print) / ISBN 2213-2317

e-ISSN 2213-2317

Journal Redox Biology

Quellenangaben Volume: 37, Article Number: 101723

Publisher Elsevier

Publishing Place Amsterdam [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants Zebrafish Core Facility Mannheim
Core Facility Live Cell Imaging Mannheim (DFG)
Metabolomics Core Technology Platform of the Excellence cluster "CellNetworks" (University of Heidelberg)
China Scholarship Council (CSC)
Deutsche Forschungsgemeinschaft