Loss of Glo2 alters the glucose metabolism in zebrafish
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ABSTRACT:
PROVIDER: PRJNA843695 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19445938.fastq.gz | Fastqsanger.gz | |||
| SRR19445939.fastq.gz | Fastqsanger.gz | |||
| SRR19445940.fastq.gz | Fastqsanger.gz | |||
| SRR19445941.fastq.gz | Fastqsanger.gz | |||
| SRR19445942.fastq.gz | Fastqsanger.gz |
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Project description:Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to D-lactate via SD-Lactoylglutathione. Recent studies have suggested Glo2 as a regulator of glycolysis, but the physiological functions of Glo2 in vivo and organ specific functions of the enzyme have not yet been evaluated. Therefore, a CRISPR/Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2-/- larvae, with no change in longevity. Adult glo2‑/- livers developed an impaired insulin signaling, indicated by a reduced hepatic P70-S6-kinase activation and reduced hepatic hexose concentration. In contrast, glo2-/- skeletal muscle remained functionally intact, compensating for the dysfunctional liver through increased glucose uptake, thereby maintaining euglycemia and preventing damage of the retina and kidney. In conclusion, the data identified Glo2 to fulfill similar but unique functions compared to Glo1 and established Glo2 as a novel target in diabetes research, regulating hepatic insulin signaling.
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Project description:Elongation of very long-chain fatty acids protein 6 (Elovl6) has been reported to be associated with clinical treatments of a variety of metabolic diseases. However, there is no systematic and comprehensive study to reveal the regulatory role of Elovl6 in the mRNA, protein and phosphorylation levels. We established the first knock-out (KO), elovl6-/-, in zebrafish. Compared with wild type (WT) zebrafish, KO presented significant higher content of whole-body lipid and lower content of fasting blood glucose. We utilized RNA-Seq, tandem mass tag (TMT) labeling-based quantitative technology, and LC-MS/MS to perform the transcriptomic, proteomic, and phosphoproteomic analyses of livers from WT and elovl6-/- zebrafish. There were 734 differentially expressed genes (DEG) and 559 differentially expressed proteins (DEP) identified out of quantifiable 47251 transcripts and 5525 proteins between elovl6-/- and WT zebrafish. Meanwhile, 680 differentially expressed phosphoproteins (DEPP) with 1054 sites were found out of quantifiable 1230 proteins with 3604 sites. GO and KEGG analysis of the transcriptomic and proteomic data further suggested that the abnormal lipid metabolism and glucose metabolism in KO were mainly related to fatty acid degradation and biosynthesis, glycolysis/gluconeogenesis and PPAR signaling pathway. In the phosphoproteomics, some phosphoproteins and kinases critical for lipid metabolism and glucose metabolism, including ribosomal protein S6 kinase (Rps6kb), mitogen-activated protein kinase14 (Mapk14), and V-akt murine thymoma viral oncogene homolog 2, -like (Akt2l), were identified. These results allowed us to catch on the regulatory networks of elovl6 on lipid and glucose metabolism in zebrafish. To our knowledge, this is the first multi-omic study of zebrafish lacking elovl6, which provides strong datasets to better understand many lipid/glucose metabolic risks posed to human health.
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Project description:Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro studies have suggested Glo2 as a regulator of glycolysis, but if Glo2 regulates glucose homeostasis and related organ specific functions in vivo has not yet been evaluated. Therefore, a CRISPR-Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2-/- larvae, without altering the glutathione metabolism or affecting longevity. Adult glo2-/- livers displayed a reduced hexose concentration and a reduced postprandial P70-S6 kinase activation, but upstream postprandial AKT phosphorylation remained unchanged. In contrast, glo2-/- skeletal muscle remained metabolically intact, possibly compensating for the dysfunctional liver through increased glucose uptake and glycolytic activity. glo2-/- zebrafish maintained euglycemia and showed no damage of the retinal vasculature, kidney, liver and skeletal muscle. In conclusion, the data identified Glo2 as a regulator of cellular energy metabolism in liver and skeletal muscle, but the redox state and reactive metabolite accumulation were not affected by the loss of Glo2.
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Project description:Dicarbonyl stress is characterized by the abnormal accumulation of dicarbonyl reactive metabolites, leading to increased modification of proteins, DNA and lipids, thereby contributing to cellular and tissue dysfunction in diabetes, diabetic complications and other diseases. glo1 knockout zebrafish exhibited moderately increased MG levels, yet this was inadequate to induce trunk vessels alterations due to elevated ALDH activity and mRNA expression levels, which partially act as compensatory mechanism. Excess 4-HNE induced pancreas dysfunction in aldh3a1 knockout zebrafish larvae, inhibiting insulin expression and thereby facilitating hyperglycemia and hyaloid vasculature alterations. To evaluate the combined function of Glo1 and Aldh3a1 in glucose homeostasis and diabetic microvasculature, glo1-/-aldh3a1-/- zebrafish were generated using CRISPR/Cas9 technology. Multiple experiments are performed regarding vasculature alterations, glucose homeostasis, transcriptome, and metabolomics in Tg(fli1:EGFP) zebrafish. glo1-/-aldh3a1-/- zebrafish larvae displayed angiogenic hyaloid vasculature caused by the elevated MG-H1 and decreased proteasomal chymotrypsin-like activity, which could be rescued by the MG-H1 scavenger L-carnosine and proteasome activator Betulinic acid treatments. In adult glo1-/-aldh3a1-/- zebrafish, impaired glucose metabolism, angiogenic retina vasculature and thickened GBM were observed. Thus, our data suggested that an important upstream factor contributing to these phenomena in the context of lacking glo1 and aldh3a1 is MG-H1, possibly through reduced proteasome activity.
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