Reduced Acrolein Detoxification in akr1a1a Zebrafish Mutants Causes Impaired Insulin Receptor Signaling and Microvascular Alterations. Issue 18 (18th July 2021)

• Record Type: Journal Article
• Authors: Qi, Haozhe; Schmöhl, Felix; Li, Xiaogang; Qian, Xin; Tabler, Christoph T.; Bennewitz, Katrin; Sticht, Carsten; Morgenstern, Jakob; Fleming, Thomas; Volk, Nadine; Hausser, Ingrid; Heidenreich, Elena; Hell, Rüdiger; Nawroth, Peter Paul; Kroll, Jens
• Is Part Of: Advanced science. Volume 8:Issue 18(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-18
• Subjects: Acrolein (ACR) -- diabetes -- impaired glucose homeostasis -- organ complications -- zebrafish; Science -- Periodicals; 505
• DOI: 10.1002/advs.202101281
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Increased acrolein (ACR), a toxic metabolite derived from energy consumption, is associated with diabetes and its complications. However, the molecular mechanisms are mostly unknown, and a suitable animal model with internal increased ACR does not exist for in vivo studying so far. Several enzyme systems are responsible for acrolein detoxification, such as Aldehyde Dehydrogenase (ALDH), Aldo‐Keto Reductase (AKR), and Glutathione S‐Transferase (GST). To evaluate the function of ACR in glucose homeostasis and diabetes, akr1a1a −/− zebrafish mutants are generated using CRISPR/Cas9 technology. Accumulated endogenous acrolein is confirmed in akr1a1a −/− larvae and livers of adults. Moreover, a series of experiments are performed regarding organic alterations, the glucose homeostasis, transcriptome, and metabolomics in Tg(fli1:EGFP ) zebrafish. Akr1a1a −/− larvae display impaired glucose homeostasis and angiogenic retina hyaloid vasculature, which are caused by reduced acrolein detoxification ability and increased internal ACR concentration. The effects of acrolein on hyaloid vasculature can be reversed by acrolein‐scavenger l ‐carnosine treatment. In adult akr1a1a −/− mutants, impaired glucose tolerance accompanied by angiogenic retina vessels and glomerular basement membrane thickening, consistent with an early pathological appearance in diabetic retinopathy and nephropathy, are observed. Thus, the data strongly suggest impaired ACR detoxification and elevated ACR concentration as biomarkers and inducers for diabetes and diabetic complications. Abstract : Acrolein (ACR) plays a critical role in diabetes processing. This work generates an akr1a1a knockout zebrafish model and shows that the loss of Akr1a1a leads to an impaired detoxification and accumulation of ACR in vivo, illustrating that internally increased ACR causes altered glucose homeostasis, which finally induces pathological retinal angiogenesis and thickening of the glomerular basement membrane (GBM).