Sortilin in Glucose Homeostasis: From Accessory Protein to Key Player?

Blondeau, Nicolas; Béraud-Dufour, Sophie; Lebrun, Patricia; Hivelin, Céline; Coppola, Thierry

doi:10.3389/fphar.2018.01561

Cited by 27 publications

(20 citation statements)

References 58 publications

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“…Nevertheless, the most significant were pathways related with autophagy and the mTOR signaling, both coded by the miR-322-5p (Figure 11a). This miRNA seems to be also important for regulation of genes involved in axon guidance, neurotrophin and insulin signaling (Figure 11a,b), which is particularly interesting due to the known functions of sortilin for glucose homeostasis and neuronal viability in the periphery [18,26].…”

Section: Differential Expression Of Small Rnas In Schwann Cells Lacking P75 Ntr or Sortilinmentioning

confidence: 99%

Modulation of Small RNA Signatures in Schwann-Cell-Derived Extracellular Vesicles by the p75 Neurotrophin Receptor and Sortilin

et al. 2020

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Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS) and are known to be involved in various pathophysiological processes, such as diabetic neuropathy and nerve regeneration, through neurotrophin signaling. Such glial trophic support to axons, as well as neuronal survival/death signaling, has previously been linked to the p75 neurotrophin receptor (p75NTR) and its co-receptor Sortilin. Recently, SC-derived extracellular vesicles (EVs) were shown to be important for axon growth and nerve regeneration, but cargo of these glial cell-derived EVs has not yet been well-characterized. In this study, we aimed to characterize signatures of small RNAs in EVs derived from wild-type (WT) SCs and define differentially expressed small RNAs in EVs derived from SCs with genetic deletions of p75NTR (Ngfr−/−) or Sortilin (Sort1−/−). Using RNA sequencing, we identified a total of 366 miRNAs in EVs derived from WT SCs of which the most highly expressed are linked to the regulation of axonogenesis, axon guidance and axon extension, suggesting an involvement of SC EVs in axonal homeostasis. Signaling of SC EVs to non-neuronal cells was also suggested by the presence of several miRNAs important for regulation of the endothelial cell apoptotic process. Ablated p75NTR or sortilin expression in SCs translated into a set of differentially regulated tRNAs and miRNAs, with impact in autophagy and several cellular signaling pathways such as the phosphatidylinositol signaling system. With this work, we identified the global expression profile of small RNAs present in SC-derived EVs and provided evidence for a regulatory function of these vesicles on the homeostasis of other cell types of the PNS. Differentially identified miRNAs can pave the way to a better understanding of p75NTR and sortilin roles regarding PNS homeostasis and disease.

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Section: Differential Expression Of Small Rnas In Schwann Cells Lacking P75 Ntr or Sortilinmentioning

confidence: 99%

Modulation of Small RNA Signatures in Schwann-Cell-Derived Extracellular Vesicles by the p75 Neurotrophin Receptor and Sortilin

et al. 2020

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“…As observed in Sort1 KO mice (Devader et al, 2016), NTS levels are expected to be up-regulated by anti-SORT1 antibody with SORT1 down-regulation activity. NTS is involved in a wide variety of biological functions, including glucose homeostasis (Blondeau et al, 2019). The NTS-mediated glucose metabolism is likely mediated through SORT1 as evidenced by the fact that Nts KO and Sort1 KO mice show resistance to obesity and hepatic steatosis, and greater insulin sensitivity on a high fat diet as common phenotypes (Rabinowich et al, 2015;Li et al, 2016).…”

Section: Effect Of Sort1 Blocking On Non-pgrn Sort1 Ligandsmentioning

confidence: 99%

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

et al. 2020

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Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.

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“…In hepatocytes, sortilin facilitates the export of very-low-density lipoproteins and thereby increases low-density lipoprotein cholesterol levels in plasma through binding to apolipoprotein B100. 12 Moreover, sortilin is involved in lipid homeostasis by suppressing intestinal cholesterol absorption, 13,14 and it has also been studied in atherosclerosis 15 and where the genetic deletion of sortilin reduces atherosclerotic plaque size. 16 In cancers, there is increasing indication that sortilin participates in the deregulation of cancer cell viability.…”

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confidence: 99%