Lipotoxicity-induced circGlis3 impairs beta cell function and is transmitted by exosomes to promote islet endothelial cell dysfunction

Xiong, Li; Chen, Li; Wu, Liting; He, Weiman; Chen, Dubo; Peng, Zishan; Jin, Li; Zhu, Xiao‐Feng; Su, Lei; Li, Yanbing; Gong, Yingying; Xiao, Hang

doi:10.1007/s00125-021-05591-4

Cited by 17 publications

(19 citation statements)

References 48 publications

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“…This circGLIS3 was shown to stimulate cell proliferation and migration and inhibit apoptosis in cultured NSCLC cells that appears to be mediated in part by the down-regulation of the tumor suppressor miR-644a. CircGlis3 RNAs appear to be also involved in the regulation of normal physiological processes, including pancreatic β cell function, as was recently reported for a circGLIS3 derived from exon 4 [ 117 ].…”

Section: Glis Circular Rnasmentioning

confidence: 64%

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

Jetten

Scoville

Kang

2022

Cells

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The GLI-Similar 1-3 (GLIS1-3) genes, in addition to encoding GLIS1-3 Krüppel-like zinc finger transcription factors, also generate circular GLIS (circGLIS) RNAs. GLIS1-3 regulate gene transcription by binding to GLIS binding sites in target genes, whereas circGLIS RNAs largely act as miRNA sponges. GLIS1-3 play a critical role in the regulation of many biological processes and have been implicated in various pathologies. GLIS protein activities appear to be regulated by primary cilium-dependent and -independent signaling pathways that via post-translational modifications may cause changes in the subcellular localization, proteolytic processing, and protein interactions. These modifications can affect the transcriptional activity of GLIS proteins and, consequently, the biological functions they regulate as well as their roles in disease. Recent studies have implicated GLIS1-3 proteins and circGLIS RNAs in the regulation of stemness, self-renewal, epithelial-mesenchymal transition (EMT), cell reprogramming, lineage determination, and differentiation. These biological processes are interconnected and play a critical role in embryonic development, tissue homeostasis, and cell plasticity. Dysregulation of these processes are part of many pathologies. This review provides an update on our current knowledge of the roles GLIS proteins and circGLIS RNAs in the control of these biological processes in relation to their regulation of normal physiological functions and disease.

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Section: Glis Circular Rnasmentioning

confidence: 64%

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

Jetten

Scoville

Kang

2022

Cells

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“…CircGLIS3 has been recently shown to play oncogenic roles in non-small cell lung cancer, bladder cancer, and glioma ( 36-39 ). Also, it is packaged into beta cell-derived exosomes and transferred to islet endothelial cells, reducing angiogenesis and contributing to type 2 diabetes development ( 40 ). Here we identified circGLIS3 as a critical factor controlling activation mechanisms of wound fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

The injury-induced circular RNA circGLIS3 activates dermal fibroblasts to promote wound healing

Toma

Wang

et al. 2022

Preprint

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Delayed skin wound healing and excessive scarring are consequences of an impaired healing process and represent a major health and economic burden worldwide. Current intervention strategies lack efficacy and suffer from high recurrence rates necessitating the investigation into alternative treatment modalities like circular RNAs (circRNAs). By RNA sequencing, we profiled circRNA expression changes during human skin wound healing as well as in keratinocytes and fibroblasts isolated from donor-matched skin and acute wounds. CircGLIS3 was found to be transiently upregulated in the dermal fibroblasts upon skin injury, which was at least partially due to the activated IL-1 signaling. Similarly, overabundant circGLIS3 expression was detected in human keloid lesions compared to the surrounding healthy skin. We found that circGLIS3 resided mainly in the cytoplasm, where it interacted with and stabilized Procollagen C-endopeptidase enhancer 1 (PCPE-1) protein to enhance TGF-beta signaling, fibroblast activation, and production of extracellular matrix - important biological processes required for wound repair. Accordingly, knockdown of circGLIS3 in human ex vivo wounds potently reduced wound contraction and delayed re-epithelialization. Collectively, we have identified a previously uncharacterized circRNA regulator of human skin wound healing that may open an avenue for circRNA-based therapeutics for abnormal scarring or nonhealing wounds.

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“…These results suggest that circRNAs may function as potential biomarkers for the diagnosis of T2DM. Additionally, lipotoxicity contributes to insulin resistance and β-cell apoptosis ( 50 ). The expression of β-cell-derived exosomal circGlis3 is increased under lipotoxic conditions; circGlis3 may be transferred to islet endothelial cells to reduce the viability, migration, and angiogenesis of these cells.…”

Section: Role Of Circrnas In T2dmmentioning

confidence: 99%

“…Moreover, an increase in exosomal circGlis3 was detected in the serum in the mouse models of DM and in individuals with T2DM. Since the serum is an easily accessible biological fluid, exosomal circGlis3 may be a potential biomarker for T2DM ( 50 ). Moreover, insulin treatment may relieve inflammation in T2DM patients.…”

Section: Role Of Circrnas In T2dmmentioning

confidence: 99%

Circular RNAs in diabetes mellitus and its complications

et al. 2022

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Diabetes mellitus (DM) is an endocrine disorder characterized by a relative or absolute lack of insulin due to the dysfunction or destruction of β-cells. DM is one of the fastest growing challenges to global health in the 21st century and places a tremendous burden on affected individuals and their families and countries. Although insulin and antidiabetic drugs have been used to treat DM, a radical cure for the disease is unavailable. The pathogenesis of DM remains unclear. Emerging roles of circular RNAs (circRNAs) in DM have become a subject of global research. CircRNAs have been verified to participate in the onset and progression of DM, implying their potential roles as novel biomarkers and treatment tools. In the present review, we briefly introduce the characteristics of circRNAs. Next, we focus on specific roles of circRNAs in type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus and diabetes-associated complications.

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Lipotoxicity-induced circGlis3 impairs beta cell function and is transmitted by exosomes to promote islet endothelial cell dysfunction

Cited by 17 publications

References 48 publications

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

The injury-induced circular RNA circGLIS3 activates dermal fibroblasts to promote wound healing

Circular RNAs in diabetes mellitus and its complications

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