Visceral Adipose Tissue E2F1-miRNA206/210 Pathway Associates with Type 2 Diabetes in Humans with Extreme Obesity

Maixner, Nitzan; Haim, Yulia; Blüher, Matthias; Chalifa‐Caspi, Vered; Veksler-Lublinsky, Isana; Makarenkov, Nataly; Yoel, Uri; Bashan, Nava; Liberty, Idit F.; Kukeev, Ivan; Dukhno, Oleg; Levy, Dan; Rudich, Assaf

doi:10.3390/cells11193046

Cited by 7 publications

(5 citation statements)

References 57 publications

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Section: Discussionmentioning

confidence: 99%

“…IGF2 [632], RPPH1 [633], PRKCB (protein kinase C beta) [634], CCL5 [635], VASH2 [636], GREM1 [637], CYP11B2 [638], HIC1 [639], PCK1 [640], HSD11B2 [641], MME (membrane metalloendopeptidase) [642], FABP1 [142], MIOX (myo-inositol oxygenase) [643], ARG2 [644], PPARGC1A [645], VNN1 [646], NOX4 [647], EPHX2 [577], DDIT4 [648], SLC2A1 [649], PFKFB2 [650], CDH2 [651], SLC22A2 [294], AQP2 [652], ANGPT1 [653], KL (klotho) [654], ACE2 [655], STC1 [656], REN (renin) [608], ERRFI1 [657], ERBB4 [658], NTNG1 [659], VCAM1 [660], PTGER3 [661] and BBOX1 [662] expression levels are associated with diabetic nephropathy. IGF2 [663], IRF7 [664], PRKCB (protein kinase C beta) [665], CCL5 [666], ACTN3 [667], AMH (anti-Mullerian hormone) [668], E2F1 [669], UBE2M [670], TP73 [671], AGER (advanced glycosylation end-product specific receptor) [672], SMPD3 [118], NR2E1 [673], ANGPTL3 [674], CYP3A5 [675], PCK1 [676], LRP2 [677], FABP1 [678], SLC22A12 [279], CYP8B1 [679], MIOX (myo-inositol oxygenase) [680], ARG2 [681], FGF1 [450], CRY1 [682], PPARGC1A [451], CRYM (crystallin mu) [683], SLC19A3 [283], FH (fumaratehydratase) [684], SLC2A9 [286], GC (GC vitamin D binding protein) [685], RGN (regucalcin) [686], MMAA (metabolism of cobalamin associated A) [687], NOX4 [688], ABHD6 [689], EPHX2 [690], DDIT4 [691], EGF (epidermal growth factor) [173], DEFB1 [692], ACE2 ...…”

Section: Discussionmentioning

confidence: 99%

“…E2F1 [496], AGTR1 [74], VCAM1 [533], hsa-mir-7847-3p [804], FOXC1 [805], USF2 [796], YY1 [806], STAT3 [807] and BRCA1 [799] have been observed in sepsis patients. Studies have shown that E2F1 [669], VCAM1 [715], AGTR1 [83], hsa-mir-221 [780], YY1 [808], STAT3 [809], PDX1 [810] and BRCA1 [811] are associated with obesity. E2F1 [719] and VCAM1 [736] are altered expressed in patients with renal ischemia.…”

Section: Discussionmentioning

confidence: 99%

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Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2024

Preprint

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Acute kidney injury (AKI) is a type of renal disease occurs frequently in hospitalized patients, which may cause abnormal renal function and structure with increase in serum creatinine level with or without reduced urine output. With the incidence of AKI is increasing. However, the molecular mechanisms of AKI have not been elucidated. It is significant to further explore the molecular mechanisms of AKI. We downloaded the GSE139061 next generation sequencing (NGS) dataset from the Gene Expression Omnibus (GEO) database. Limma R bioconductor package was used to screen the differentially expressed genes (DEGs). Then, the enrichment analysis of DEGs in Gene Ontology (GO) function and REACTOME pathways was analyzed by g:Profiler. Next, the protein-protein interaction (PPI) network and modules was constructed and analyzed, and the hub genes were identified. Next, the miRNA-hub gene regulatory network and TF-hub gene regulatory network were built. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. Overall, 956 DEGs were identified, including 478 up regulated and 478 down regulated genes. The enrichment functions and pathways of DEGs involve primary metabolic process, small molecule metabolic process, striated muscle contraction and metabolism. Topological analysis of the PPI network and module revealed that hub genes, including PPP1CC, RPS2, MDFI, BMI1, RPL23A, VCAM1, ALB, SNCA, DPP4 and RPL26L1, might be involved in the development of AKI. miRNA-hub gene and TF-hub gene regulatory networks revealed that miRNAs and TFs including hsa-mir-510-3p, hsa-mir-6086 and mir-146a-5p, MAX and PAX2, might be involved in the development of AKI. Various known and newtherapeutic targets were obtained via network analysis. The results of the current investigation might be beneficial for the diagnosis and treatment of AKI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2024

Preprint

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“… 42 Maixner et al demonstrated that E2F1 could upregulate the miR-206 and miR-210-5p expression of human visceral adipose tissue, which might contribute to extreme obesity. 43 These researches proved that E2F1 could not only regulate the transcription of miRNAs, but also affect the paracrine expression profile of ADSCs. However, it remains ambiguous how E2F1 regulates the miRNA expression of ADSCs and ADSC-Exos.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from E2F1–/– Adipose-Derived Stem Cells Promote Skin Wound Healing via miR-130b-5p/TGFBR3 Axis

Yu,

Wu,

Zhang

et al. 2023

IJN

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Background Skin wound is a widespread health problem and brings extraordinary burdens to patients. Exosomes derived from adipose-derived stem cells (ADSC-Exos) are considered promising strategies for repairing skin wounds. E2F1 is a member of the E2F family of transcription factors involved in cell growth and apoptosis. E2F1 deficiency in mice enhances wound healing by improving collagen deposition and angiogenesis. Additionally, E2F1 can regulate the transcription and paracrine activity of multiple miRNAs, which will inevitably reshape the paracrine expression profile of ADSC-Exos. This study aimed to investigate the impact of transcription factor E2F1 deficiency on the functions of ADSC-Exos in promoting wound healing. Methods First, we obtained ADSCs from subcutaneous adipose tissues of WT and E2F1 –/– C57BL/6 mice and separated their exosomes, denoted as ADSC WT -Exos and ADSC E2F1-/- -Exos. The wound healing effects of ADSC WT -Exos and ADSC E2F1-/- -Exos in full-thickness skin wound models were investigated by wound images, H&E staining, and immunohistochemical staining. For the in vitro study, the abilities of ADSC WT -Exos and ADSC E2F1-/- -Exos to promote cell activities, collagen formation, and angiogenesis were evaluated. The potential mechanism by which ADSC E2F1-/- -Exos promote wound healing was determined by miRNA sequencing, ChIP‒qPCR, and dual-luciferase assays. Results ADSC E2F1-/- -Exos accelerated wound healing by promoting collagen formation and angiogenesis. As a result, compared with the lower wound healing rate of 30.5% within 7 days in the control group and 42.3% in the ADSC WT -Exo group, ADSC E2F1-/- -Exos significantly increased the wound healing rate to 72.5%. In vitro, ADSC E2F1-/- -Exos activated the function of fibroblasts and vascular endothelial cells. The loss of E2F1 promoted miR-130b-5p expression in ADSC E2F1-/- -Exos through transcriptional regulation. MiRNA high-throughput sequencing identified 12 differently expressed miRNAs between ADSC E2F1-/- and ADSC WT . ADSC E2F1-/- -Exos enhanced fibroblast activities via the miR-130b-5p/TGFBR3 axis and TGF-β activation. Conclusion Our results indicated that ADSC E2F1-/- -Exos effectively promoted wound healing by regulating the miR-130b-5p/TGFBR3 axis, thus providing a novel strategy of gene-engineered stem cell exosomes for accelerating wound healing.

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“…Currently, miR-210-5p has been reported to be markedly upregulated in the exosomes derived from ATM ( 17 ), and exosomal miRNA-210 disrupts adipocyte glucose mitochondrial oxidation and glucose uptake ( 12 ). Moreover, miR-210-5p is correlated with fasting glucose levels and fasting insulin ( 19 ). However, the expression and molecular mechanisms of miR-210-5p in rats born SGA with CUG (CUG-SGA) remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth

Xiong¹,

Liu²,

Song³

et al. 2023

Transl Pediatr

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Background: Insulin resistance has been implicated in the pathogenesis of children born small for gestational age (SGA) with catch-up growth (CUG). Adipose tissue macrophages (ATMs) regulate insulin resistance by secreting exosomes containing microRNA (miRNA) cargo; however, their pathogenic roles and molecular mechanism are not fully understood. This study aimed to investigate the role of miR-210-5p in rats born SGA with CUG and insulin resistance. Methods:The dietary needs of pregnant rats were restricted to ensure the birth of SGA rats. Transmission electron microscopy (TEM) and Western blot analysis were used to identify the exosomes from ATMs of CUG-SGA and adequate-for-gestational-age (AGA) rats. PKH-67 staining was performed to confirm the uptake of exosomes. miR-210-5p expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Glucose uptake and output were detected with glucose uptake and output assays, respectively. Insulin resistance was detected with glucose and insulin tolerance tests in vivo. The interaction between miR-210-5p and SID1 transmembrane family member 2 (SIDT2) was validated with dual-luciferase reporter assay.Results: miR-210-5p was observed to be highly expressed in the exosomes derived from the ATMs of CUG-SGA rats. ATM-derived exosomes can serve as vehicles to deliver miR-210-5p into adipocytes, myocytes, and hepatocytes, where it can enhance cellular insulin resistance. SIDT2 was identified as a direct target gene of miR-210-5p. The miR-210-5p-induced insulin resistance was reversed by the restored SIDT2 expression. However, overexpression of SIDT2 abolished the inhibitory effect of CUG-SGA-ATM-exosomal miR-210-5p on insulin sensitivity in vivo.Conclusions: ATM-derived exosomal miR-210-5p promoted insulin resistance in CUG-SGA rats by targeting SIDT2, which may act as a new potential therapeutic target for children born SGA with CUG.

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Visceral Adipose Tissue E2F1-miRNA206/210 Pathway Associates with Type 2 Diabetes in Humans with Extreme Obesity

Cited by 7 publications

References 57 publications

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Exosomes Derived from E2F1–/– Adipose-Derived Stem Cells Promote Skin Wound Healing via miR-130b-5p/TGFBR3 Axis

Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth

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