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The function and mechanism of aldh9a1b in diabetes

ABSTRACT: Reactive aldehydes such as 4-HNE, MDA and acrolein are implicated in the pathological development of diabetes as their widespread and universally exposed characteristics. Trans, trans-2,4-decadienal (tt-DDE) come from lipid peroxidation of omega-6 and is most abundant aldehyde in cooking oil fumes, while, its role in diabetes remained unknown. Aldh9a1 is a cytosolic enzyme that catalyze the NAD+-dependent oxidation of a variety of aldehydes and has its homology aldh9a1b in zebrafish. To investigate the function of endogenous and exogenous tt-DDE, aldh9a1b knockout zebrafish are established using CRISPR/Cas9 technology. TT-DDE was confirmed to act as substrate for aldh9a1b and a series of experiments are performed on a histological, metabolomic and transcriptomic level in aldh9a1b-/- zebrafish. Both aldh9a1b-/- larvae and adult fish displayed abnormal retinal vasculature and impaired glucose homeostasis, which are caused by tt-DDE induced downregulated insulin signaling pathway. Furthermore, the abnormal hyaloid vasculature in the fish can be reversed by insulin receptor sensitizer and metformin exhibited strongest effects among them. Altogether, these results identified tt-DDE as the preferred substrate for aldh9a1b, which subsequently causes microvascular damage and impaired glucose metabolism by insulin resistance.

ORGANISM(S): Danio rerio

PROVIDER: GSE223340 | GEO | 2023/12/08

REPOSITORIES: GEO

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Project description:Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cells function may have ultimate consequences. 3-methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue™ assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10µM) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 7540 proteins were identified in which the abundance of 87 proteins in unstimulated Leydig cells and 146 proteins in LH-stimulated Leydig cells were found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathion-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.

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The function and mechanism of aldh9a1b in diabetes

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