The RhoGAP Stard13 controls insulin secretion through F-actin remodeling

Naumann, Heike; Rathjen, Thomas; Poy, Matthew N.; Spagnoli, Francesca M.

doi:10.1016/j.molmet.2017.12.013

Cited by 18 publications

(15 citation statements)

References 42 publications

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“…STARD13 encodes the protein StAR-related lipid transfer protein 13, a Rho GTPase-activating protein closely associated with hepatic cancer ( 80 ). Besides being linked with actin cytoskeletal organization, this protein also seems to influence other biological activities ( 81 ), such as insulin secretion ( 82 ), and induction of mitochondrial phosphatidylglycerolphosphate synthase activation in response to ceramides ( 83 ). This may be particularly relevant in the adipocyte’s metabolic deregulation, as ceramides play an important role in glucose uptake and metabolism ( 84 ).…”

Section: Resultsmentioning

confidence: 99%

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

et al. 2021

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BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability.ScopeThe aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches.MethodsOriginal data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was compiled.ResultsWe catalogued more than two thousand differentially methylated regions (DMRs; above the cut-off of 5%) in the AT of individuals with MUHO compared to individuals with MHO. These DNA methylation changes were less likely to occur around the promoter regions and were enriched at loci implicated in intracellular signaling (signal transduction mediated by small GTPases, ERK1/2 signaling and intracellular trafficking). We also identified a network of seven transcription factors that may play an important role in targeting DNA methylation changes to specific genes in the AT of subjects with MUHO, contributing to the pathogeny of obesity-related IR/T2D. Furthermore, we found differentially methylated CpG sites at 8 genes that were present in AT and whole blood, suggesting that DMRs in whole blood could be potentially used as accessible biomarkers of MUHO.ConclusionsThe overall evidence linking epigenetic alterations in key tissues such AT to metabolic complications in human obesity is still very limited, highlighting the need for further studies, particularly those focusing on epigenetic marks other than DNA methylation. Our initial analysis suggests that DNA methylation patterns can potentially discriminate between MUHO from MHO and provide new clues into why some people with obesity are less susceptible to dysglycemia. Identifying AT-specific epigenetic targets could also lead to novel approaches to modify the progression of individuals with obesity towards metabolic disease.Systematic Review RegistrationPROSPERO, identifier CRD42021227237.

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Section: Resultsmentioning

confidence: 99%

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

et al. 2021

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“…Finally, the values were normalized by the number of cells. For the analysis of filamentous actin (F-actin), the fluorescence intensity of F-actin in images on split channels were measured in ImageJ and normalized by the number of cells 38 . We performed morphological analysis from at least three randomly selected images per group in three independent experiments (containing total number of cells ranging from 1,089 to 1,521 cells per group).…”

Section: Methodsmentioning

confidence: 99%

Umbilical cord-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of LPS-activated microglia via PI3K/Akt/Rho GTPase pathway

et al. 2021

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Microglia are the immune cells in the central nervous system surveying environment and reacting to various injuries. Activated microglia may cause impaired synaptic plasticity, therefore modulating and restoring them to neutral phenotype is crucial to counteract a pro-inflammatory, neurotoxic state. In this study, we focused on elucidating whether human umbilical cord (UC) -derived mesenchymal stromal cells (MSCs) can exert immunomodulatory effect and change the phenotype of activated microglia. Primary culture of microglia was activated by lipopolysaccharide (LPS) and was co-cultured with three lots of MSCs. We investigated immunomodulation, actin dynamics and phagocytic capacity of activated microglia, and examined change of Rho GTPase in microglia as the mechanism. MSCs suppressed the expression of IL-1β and pNFκB in LPS-activated microglia, and conversely elevated the expression of IL-1β in resting-surveying microglia with lot-to-lot variation. Morphological and phagocytotic analyses revealed that LPS stimulation significantly increased active Rho GTPase, Rac1, and Cdc42 levels in the microglia, and their morphology changed to amoeboid in which F-actin spread with ruffle formation. The F-actin spreading persisted after removal of LPS stimulation and reduced phagocytosis. On the other hand, MSC co-culture induced bimodal increase in active Rac1 and Cdc42 levels in LPS-activated microglia. Moreover, extended ruffles of F-actin shrinked and concentrated to form an actin ring, thereby restoring phagocytosis. We confirmed inhibition of the PI3K/Akt pathway attenuated F-actin dynamics and phagocytosis restored by MSCs. Overall, we demonstrated that MSCs immunomodulated microglia with lot-to-lot variation, and changed the phenotype of LPS-activated microglia restoring actin dynamics and phagocytosis by increase of active Rho GTPase.

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“…3 C). F-actin, the major component of the cytoskeleton microfilament [19] , was displayed to be tentacle-like and more polarity detected by phalloidin staining in JUP-knocked down NCI-87 cells ( Fig. 3 D), which accompanied with notably decreased epithelial marker E-cadherin and β-catenin and enhanced mesenchymal marker Vimentin and Fibronectin in the JUP-knocked down NCI-87 cells ( Fig.…”

Section: Resultsmentioning

confidence: 94%