ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation

Wang, Xuan; Younis, Shady; Cen, Jing; Wang, Yun; Krizhanovskii, Camilla; Andersson, Leif; Welsh, Nils

doi:10.1007/s00125-021-05517-0

Cited by 15 publications

(13 citation statements)

References 39 publications

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“…In CNS, Egr1 mRNA expression level was significantly decreased in cognitive dysfunction model of T2DM mice [35]. Zbed6, zinc finger BED domain-containing protein 6, established a role in regulating IGF2 mRNA expression and insulin production, maintaining beta cell area, and reducing excess mitochondrial activation [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods. In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results. A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion. Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Chromatin immunoprecipitation (ChIP) sequencing using murine C2C12 cells indeed demonstrated that ZBED6 may regulate additional 1200 ZBED6 binding sites other than IGF2 [ 4 ]. ZBED6 regulates beta cell area and excess mitochondrial activation by controlling the cell cycle gene PTTG1 and the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) in mice, which occurred independently from ZBED6 effects on IGF2 gene expression [ 13 ]. However, the functional role of ZBED6 in pig besides its important role for regulating IGF2 expression is still poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets

et al. 2021

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ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6−/−) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6−/− pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6-/- pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6-/- pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6-/- pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively.

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“…While our findings support the notion that NOX4 is harmful in stressed human beta-cells, it is also possible that short-term NOX 4 activation mediates beneficial effects. Mitochondrial overactivation and metabolic maladaptation have recently been suggested to be an early response to chronic glucose stress in beta cells [ 27 ], and protecting mitochondria from this nutrient overload may preserve normal beta-cell function [ 28 ]. NOX4 inhibition might modulate the mitochondrial activity of beta-cells enough for them to overcome the stress from a diabetic milieu.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells

et al. 2021

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Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-βH1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-βH1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-βH1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets.

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ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation

Cited by 15 publications

References 39 publications

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets

Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells

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