Acidic Sialidase Activity Is Aberrant in Obese and Diabetic Mice

Natori, Yujin; Ohkura, Naoki; Nasui, Miwako; Atsumi, Gen‐ichi; Kihara-Negishi, Fumiko

doi:10.1248/bpb.b12-00995

Cited by 18 publications

(12 citation statements)

References 30 publications

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“…We previously found increased Neu1 activity during adipogenesis in 3T3-L1 adipocytes and in the epididymal fat of obese and diabetic mice (Natori et al 2013). According to the present study, high Neu1 activity might reduce Plin1 protein expression, stabilization and/or phosphorylation in the epididymal fat of obese and diabetic mice.…”

Section: Discussionsupporting

confidence: 73%

“…Cell culture and differentiation Murine 3T3-L1 preadipocytes (DS Pharma Biomedical Co. Ltd., Osaka, Japan) were cultured and differentiated for eight days postinduction as described (Natori et al 2013). Briefly, 3T3-L1 preadipocytes were cultured with high-glucose Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum (Biowest, Nuaill e, France) and a solution of 1% penicillin and 1% streptomycin (PS) (Wako Pure Chemical Industries Co. Ltd., Osaka, Japan) for two days after reaching confluence.…”

Section: Methodsmentioning

confidence: 99%

“…The catabolic role of Neu1 in lysosomes is established, and Neu1 in the plasma membrane plays a role in cell proliferation, differentiation, elastogenesis and inflammation (Pshezhetsky & Ashmarina 2013). The activity of Neu1 is increased during adipogenesis in 3T3-L1 preadipocytes, and Neu1 activity is aberrant in the epididymal fat and livers of obese and diabetic mice (Natori et al 2013). Indeed, Neu1 activity is aberrant in several disorders, such as lysosomal storage disorder and autoimmune diseases, and the malignancy and metastasis of cancer cells (Pshezhetsky & Ashmarina 2013;Bonten et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

2017

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Fatty acids are stored within adipocytes in lipid droplets (LDs) as triacylglycerol (TG), which is converted to free fatty acid (FFA) and glycerol via lipolysis. Increased plasma FFA levels in obesity are associated with several clinical conditions. We previously found that Neu1 activity is aberrant in the epididymal fat and liver of obese and diabetic mice. Here, we examined involvement of Neu1 in lipolysis in 3T3-L1 adipocytes. Small interfering RNA against Neu1 was introduced into adipocytes, and glycerol concentrations were measured in the culture medium. We then assessed the effects of Neu1 knockdown on lipolytic protein expression and phosphorylation, as well as interactions between perilipin 1 (Plin1) and hormone-sensitive lipase (HSL) after isoproterenol (IS) stimulation. Interactions between Neu1 and Plin1 were analyzed by immunoprecipitation and immunofluorescent imaging using adipocytes transfected with pCMV6-mNeu1-myc-DYKDDDDK (mNeu1DDK). Neu1 knockdown increased glycerol concentrations in culture media and Plin1 phosphorylation in whole lysates of IS-stimulated cells. Neu1 knockdown increased interaction between Plin1 and HSL after IS stimulation whereas that between Neu1 and Plin1 on LD observed under basal conditions was lost. These results suggest that Neu1 inhibits lipolysis induced by β-adrenergic stimulation in adipocytes via interactions with Plin1 on LD.

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Section: Discussionsupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

2017

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“…Recently, there has been a growing interest in the potential role of neuraminidases (sialidases) in the regulation of metabolic pathways [9] , [10] , [11] , [12] , [13] , [14] , including glucose homeostasis [15] , [16] , [17] . Neuraminidases catalyze the removal of sialic acid residues from glycan chains of glycoproteins, oligosaccharides and sialylated glycolipids, and together with sialyltransferases modulate molecular and cellular recognition events (reviewed in [18] ).…”

Section: Introductionmentioning

confidence: 99%

Neuraminidase 1 activates insulin receptor and reverses insulin resistance in obese mice

Fougerat

Pan

Smutova

et al. 2018

Molecular Metabolism

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ObjectivesNeuraminidase 1 (NEU1) cleaves terminal sialic acids of glycoconjugates during lysosomal catabolism. It also modulates the structure and activity of cellular surface receptors affecting diverse pathways. Previously we demonstrated that NEU1 activates the insulin receptor (IR) and that NEU1-deficient CathAS190A-Neo mice (hypomorph of the NEU1 activator protein, cathepsin A/CathA) on a high-fat diet (HFD) develop hyperglycaemia and insulin resistance faster than wild-type animals. The major objective of the current work was to reveal the molecular mechanism by which NEU1 desialylation activates the IR and to test if increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance.MethodsTo test if desialylation causes a conformational change in the IR dimer we measured interaction between the receptor subunits by Bioluminescence Resonance Energy Transfer in the HEK293T cells either overexpressing NEU1 or treated with the NEU1 inhibitor. The influence of NEU1 overexpression on insulin resistance was studied in vitro in palmitate-treated HepG2 cells transduced with NEU1-expressing lentivirus and in vivo in C57Bl6 mice treated with HFD and either pharmacological inducer of NEU1, Ambroxol or NEU1-expressing adenovirus. NEU1-deficient CathAS190A-Neo mice were used as a control.ResultsBy desialylation of IR, NEU1 induced formation of its active dimer leading to insulin signaling. Overexpression of NEU1 in palmitate-treated HepG2 cells restored insulin signaling, suggesting that increased NEU1 levels may reverse insulin resistance. Five-day treatment of glycemic C57Bl6 mice receiving HFD with the activator of the lysosomal gene network, Ambroxol, increased NEU1 expression and activity in muscle tissue, normalized fasting glucose levels, and improved physiological and molecular responses to glucose and insulin. Ambroxol did not improve insulin sensitivity in obese insulin-resistant CathAS190A-Neo mice indicating that the Ambroxol effect is mediated through NEU1 induction. Sustained increase of liver NEU1 activity through adenovirus-based gene transfer failed to attenuate insulin resistance most probably due to negative feedback regulation of IR expression.ConclusionTogether our results demonstrate that increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance suggesting that a pharmacological modulation of NEU1 activity may be potentially explored for restoring insulin sensitivity and resolving hyperglycemia associated with T2DM.

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“…To date, 50 causative mutations are reported in HGMD [13] database, most of which are missense variants, suggesting a high allelic heterogeneity. Recent studies have also defined a role for NEU1 in various multifactorial diseases, such as atherosclerosis [14], obesity [15], diabetes [16], [17] and Alzheimer's disease [18], as well as in other important cellular processes, such as cancer and immunological response [19]. To further characterize the NEU1 gene and identify functionally relevant protein isoforms, we decided to study its genetic variability in the human population.…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of New Putative Pathogenic Variants in the Neu1 Sialidase Gene Affecting Enzyme Function and Subcellular Localization

et al. 2014

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The NEU1 gene is the first identified member of the human sialidases, glycohydrolitic enzymes that remove the terminal sialic acid from oligosaccharide chains. Mutations in NEU1 gene are causative of sialidosis (MIM 256550), a severe lysosomal storage disorder showing autosomal recessive mode of inheritance. Sialidosis has been classified into two subtypes: sialidosis type I, a normomorphic, late-onset form, and sialidosis type II, a more severe neonatal or early-onset form. A total of 50 causative mutations are reported in HGMD database, most of which are missense variants. To further characterize the NEU1 gene and identify new functionally relevant protein isoforms, we decided to study its genetic variability in the human population using the data generated by two large sequencing projects: the 1000 Genomes Project (1000G) and the NHLBI GO Exome Sequencing Project (ESP). Together these two datasets comprise a cohort of 7595 sequenced individuals, making it possible to identify rare variants and dissect population specific ones. By integrating this approach with biochemical and cellular studies, we were able to identify new rare missense and frameshift alleles in NEU1 gene. Among the 9 candidate variants tested, only two resulted in significantly lower levels of sialidase activity (p<0.05), namely c.650T>C and c.700G>A. These two mutations give rise to the amino acid substitutions p.V217A and p.D234N, respectively. NEU1 variants including either of these two amino acid changes have 44% and 25% residual sialidase activity when compared to the wild-type enzyme, reduced protein levels and altered subcellular localization. Thus they may represent new, putative pathological mutations resulting in sialidosis type I. The in silico approach used in this study has enabled the identification of previously unknown NEU1 functional alleles that are widespread in the population and could be tested in future functional studies.

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Acidic Sialidase Activity Is Aberrant in Obese and Diabetic Mice

Cited by 18 publications

References 30 publications

Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

Neuraminidase 1 activates insulin receptor and reverses insulin resistance in obese mice

In Silico Identification of New Putative Pathogenic Variants in the Neu1 Sialidase Gene Affecting Enzyme Function and Subcellular Localization

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