Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans
Bowen Lou,
Mike Boger,
Katrin Bennewitz,
Carsten Sticht,
Stefan Kopf,
Jakob Morgenstern,
Thomas Fleming,
Rüdiger Hell,
Zuyi Yuan,
Peter Paul Nawroth,
Jens Kroll
Affiliations
Bowen Lou
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710048, China
Mike Boger
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Katrin Bennewitz
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Carsten Sticht
Center for Medical Research (ZMF), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Stefan Kopf
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
Jakob Morgenstern
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
Thomas Fleming
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
Rüdiger Hell
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany
Zuyi Yuan
Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710048, China
Peter Paul Nawroth
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, München, Heidelberg, Germany
Jens Kroll
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Corresponding author. European Center for Angioscience (ECAS), Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Ludolf Krehl Str.13–17, 68167, Mannheim, Germany.
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.
