TY  - GEN
A1  - Wohlfart, David Philipp
CY  - Heidelberg
ID  - heidok32258
TI  - Accumulation of Endogenous Acetaldehyde in Aldehyde 
Dehydrogenase 2 Gene Knockout Zebrafish contributes to 
Microvascular Complications and Impaired Glucose Metabolism
N2  - Reactive carbonyl species (RCS) are spontaneously formed during metabolism and modify and impair the function of DNA, proteins, and lipids, leading to several organ complications. The most prominent constituent of this class is methylglyoxal (MG) with its ability to produce and cause the accumulation of advanced glycation endproducts (AGEs). Methylglyoxal is a non-enzymatic byproduct of glycolysis, amino acids, lipids and more, and can be detoxified primarily through the glyoxalase system, aldehyde dehydrogenases (Aldh) and aldo-ketoreductases (Akr). Studies about the glyoxalase system have recently been completed for mice, zebrafish and Drosophila and reveal that compensatory mechanisms like Aldh and Akr will significantly reduce complications during loss of function of the glyoxalase system. However, the effect of endogenous elevation of these various RCS like acetaldehyde (AA), 4-hydroxynonenal (4-HNE), and acrolein (ACR) are currently poorly understood. Therefore, this study aimed to identify the specific primary RCS detoxification target of different Aldh family members and to investigate the impact of endogenous elevation on organ complications and glucose metabolism in vivo.
In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo1), 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. The isoform aldh2.1 was compensatory upregulated in glo1 /  animals as well and therefore implemented as a single gene knockout mutant in zebrafish. The knockout mutant was analyzed on a histological, metabolic and transcriptional level, because aldh2.1-/- zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Furthermore, expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediated an activation of angiogenesis. However, the 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 akin to hypoglycemia. 
In conclusion, the data have identified AA as the preferred substrate for Aldh2.1?s detoxification ability, which subsequently caused microvascular organ damage and impaired glucose metabolism independently of ethanol exposure.
Y1  - 2022///
AV  - public
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/32258/
ER  -