PUBLICATION
Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease
- Authors
- Qian, X., Klatt, S., Bennewitz, K., Wohlfart, D.P., Lou, B., Meng, Y., Buettner, M., Poschet, G., Morgenstern, J., Fleming, T., Sticht, C., Hausser, I., Fleming, I., Szendroedi, J., Nawroth, P.P., Kroll, J.
- ID
- ZDB-PUB-231208-3
- Date
- 2023
- Source
- Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11(4): e2302325 (Journal)
- Registered Authors
- Kroll, Jens
- Keywords
- Aldh9a1b, diabetic retinopathy, insulin resistance, omega-6 fatty acids, prediabetes, trans, trans-2,4-decadienal, zebrafish
- Datasets
- GEO:GSE223340
- MeSH Terms
-
- Aldehydes*
- Animals
- Fatty Acids, Omega-6
- Gluconeogenesis
- Insulin*
- Insulin Resistance*
- Zebrafish
- PubMed
- 38059818 Full text @ Adv Sci (Weinh)
Citation
Qian, X., Klatt, S., Bennewitz, K., Wohlfart, D.P., Lou, B., Meng, Y., Buettner, M., Poschet, G., Morgenstern, J., Fleming, T., Sticht, C., Hausser, I., Fleming, I., Szendroedi, J., Nawroth, P.P., Kroll, J. (2023) Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 11(4):e2302325.
Abstract
Omega-6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega-6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans-2,4-decadienal (tt-DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4-hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt-DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt-DDE. Loss of Aldh9a1b increased tt-DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b-/- zebrafish. Transcriptomic and metabolomic analyses revealed that tt-DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt-DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt-DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping