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Loss of Glo2 alters the glucose metabolism in zebrafish

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE205085 | GEO | 2023/03/15

REPOSITORIES: GEO

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Hepatic dysregulation of glyoxalase 1 in preclinical models and patients with non-alcoholic fatty liver disease

Project description:Background & Aims: Although non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, aspects of its molecular pathogenesis are unknown and clinical biomarkers for early diagnosis and accurate disease staging remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of NAFLD and explore the utility of novel candidate biomarkers in NAFLD patients. Methods: Liver protein fractions were analyzed in a relative quantitative proteomic approach utilizing isobaric tags for relative and absolute quantitation (iTRAQ) labeling combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential expression was confirmed independently by western blotting and immunohistochemistry, first in mouse sections and then in biopsies from paediatric NAFLD patients. Candidate serum biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling we identified decreased expression of hepatic glyoxalase 1 (GLO1) in an animal model of NAFLD. GLO1 protein levels were also found reduced in tissue biopsies from pediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid-loading in hepatocytes, GLO1 is first hyper-acetylated then ubiquitinylated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 62 biopsy-confirmed adult NAFLD patients serum levels of the primary methylglyoxal-derived advanced glycated endproduct, hydroimidazolone (MG-H1) were found strongly correlated with body mass index (r=0.619, p<0.0001). Conclusions: We characterize, for the first time, the post-translational modification and regulation of GLO1 expression in response to hepatic lipid loading with functional consequences in NAFLD patients.

2018-02-16 | PXD001442 | Pride

Glyoxalase 1 Knockout Promotes Age- and Sex-dependent Obesity and Metabolic Dysfunction

Project description:Glyoxalase 1 (Glo1) is a critical enzyme responsible for the clearance of toxic dicarbonyls, which modify proteins to produce advanced glycation end products (AGEs). Glo1 has been recently implicated in the progression of metabolic disorders, however underlying mechanisms are poorly understood. We aim to investigate the role of Glo1 in metabolic perturbations and determine whether AGEs mediate the Glo1 activities in obesity and metabolic health.

2018-08-03 | GSE118034 | GEO

Comparison of RNA responses to fentanyl in two mouse strains

Project description:An increase in opioid-overdose deaths was evident before the COVID-19 pandemic, and has escalated since its onset. Fentanyl, a highly potent synthetic opioid, is the primary driver of these recent trends. The current study used two inbred mouse strains, C57BL/6 J and A/J, to investigate the genetics of behavioral responses to fentanyl. Mice were tested for conditioned place preference and fentanyl-induced locomotor activity. C57BL/6J mice formed a conditioned place preference to fentanyl injections and fentanyl increased their activity. Neither effect was noted in A/J mice. We conducted RNA-sequencing on the nucleus accumbens of mice used for fentanyl-induced locomotor activity. Surprisingly, we noted few differentially expressed genes using treatment as the main factor. However many genes differed between strains. We validated differences in two genes: suppressor APC domain containing 1 (Sapcd1) and Glyoxalase 1 (Glo1), with quantitative PCR on RNA from the nucleus accumbens and prefrontal cortex. In both regions A/J mice had significantly higher expression of both genes than did C57BL/6 J. In prefrontal cortex, fentanyl treatment decreased Glo1 mRNA. Glyoxalase 1 catalyzes the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, is associated with anxiety and activity levels, and its inhibition reduces alcohol intake. We suggest that future studies assess the ability of Glo1 and related metabolites to modify opioid intake.

2023-01-10 | GSE222569 | GEO

Proteomic response to cytotoxicity of methylglyoxall

Project description:Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. MG is increased to cytotoxic levels by clinical anticancer drugs, contributing to their mechanism of action. We investigated the role of the proteomic response to MG in mediating cytotoxicity. The proteomic response to MG-induced cytotoxicity was explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. MG induced decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. We conclude that MG-mediated cytotoxicity targets the spliceosome.

2021-11-02 | PXD029315 | Pride

Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

Project description:Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

2021-07-20 | GSE149585 | GEO

Methylglyoxal modification of TrkB enhances synaptic plasticity in prefrontal cortex and promotes resilience to chronic stress

Project description:Major depressive disorder (MDD) is a severe psychiatric illness that affects about 16 percent of the global population. Despite massive efforts, unravelling the pathophysiology of MDD and developing effective treatments is still a huge challenge. Here, we report a novel therapeutic axis of methylglyoxal (MGO)/tropomyosin receptor kinase B (TrkB) for treating MDD. As an endogenous metabolite, MGO was demonstrated directly binding to the extracellular domain of TrkB, provoking its dimerization and autophosphorylation. This rapidly enhances the expression of brain-derived neurotrophic factor (BDNF) and forms a BDNF-positive feedback loop. Low-dose treatment of MGO effectively promotes the hippocampal neurogenesis and exhibits sustained antidepressant effects in chronic unpredictable mild stress rat models. In addition, the modulation on MGO concentration by overexpression or inhibition of Glyoxalase 1 (GLO1) has been demonstrated associated with depression behaviors in rats. Furthermore, we also identified a natural product luteolin and its derivative lutD as potent inhibitors of GLO1 and explored their precise binding modes. Our findings reveal a novel regulatory mechanism underlying MDD and depict principles for the rational design of new antidepressants targeting GLO1.

2018-09-06 | GSE119482 | GEO

A combined proteomic and targeted analysis unravels new toxic mechanisms for zinc oxide nanoparticles in macrophages

Project description:The cellular responses of the J774 macrophage cell line to zinc oxide and zirconium oxide nanoparticles have been studied by a comparative quantitative, protein level based proteomic approach. The most prominent results have been validated by targeted approaches. These approaches have been carried out under culture conditions that stimulate mildly the aryl hydrocarbon receptor, thereby mimicking conditions that can be encountered in vivo in complex environments. The comparative approach with two nanoparticles allows to separate the common responses, which can be attributed to the phagocytosis event per se, from the response specific to each type of nanoparticles. The zinc-specific responses are the most prominent ones and include mitochondrial proteins too, but also signaling molecules such as MyD88, proteins associated with methylglyoxal detoxification (glyoxalase 2, aldose reductase) and deoxyribonucleotide hydrolases. The in cellulo inhibition of GAPDH by zinc was also documented, representing a possible source of methylglyoxal in the cells, leading to an increase in methylglyoxal-modified DNA bases. These observations may be mechanistically associated with the genotoxic effect of zinc and its selective effects on cancer cells

2022-03-01 | PXD002764 | Pride

Profiling of Methylglyoxal Blood Metabolism and Advanced Glycation End-Product Proteome using a Chemical Probe

Project description:Methylglyoxal (MG) is a toxic byproduct of the glycolytic pathway and is quantitatively the most important precursor to advanced glycation end-products (AGEs). Insight into which proteins and in particular their individual modification sites are central to understand the involvement of MG and AGE in diabetes and aging related diseases. Here, we present a method to simultaneously monitor protein AGE formation in biological samples by employing an alkyne-labeled methylglyoxal probe. We apply the method to blood and plasma to demonstrate the impact of blood cell glyoxalase activity on plasma protein AGE formation. We move on to isolate proteins modified by the MG probe and accordingly can present the first general inventory of more than 100 proteins and 300 binding sites of the methylglyoxal probe on plasma as well as erythrocytic proteins.

2019-07-31 | PXD011314 | Pride

Proteome and secretome of HepaRG cells

Project description:Primary human hepatocytes, the gold standard for in vitro studies of liver-related functions, suffer from uncertain availability and high variability in cell activity. Over years, a number of alternative hepatic cell lines have lost major liver-like functions, but not HepaRG cells. Therefore, their increasing use worldwide today arouses the need for establishing a reference functional status of differentiated HepaRG cells known as HPR116, which originate from the initial cell bank. Deep proteome and secretome analyses enabled us to show that they nicely express, at levels generally close to those in primary hepatocytes, master regulators of the hepatic phenotype, structural elements that ensure liver-like polarisation and factors supporting their transdifferentiation properties. Their highly differentiated status, mitochondrial functionality, hepatokine secretion ability and response to insulin was verified. Overall, the HepaRG cell system appears as robust surrogate cell system to primary hepatocytes, versatile enough to study not only xenobiotic detoxification but also the control of hepatic energy metabolism, secretory function and disease-related signalling pathways.

2019-02-27 | PXD010304 | Pride

Effects of the insulin degrading enzyme silencing on the transcriptome of HepG2 cells

Project description:Insulin degrading enzyme (IDE) is a major enzyme responsible for insulin degradation in the liver. The modulation of insulin degrading enzyme activity is hypothesized to be a link between T2DM and liver cancer. Results provide insight into role of IDE in proliferation and other cell functions.

2014-09-06 | GSE61142 | GEO

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