g(m3)-ganglioside and Inflammation

Chronic inflammation plays an important role in the pathogenesis of obesity and metabolic disorders. In obesity, pattern-recognition receptors in innate immune system, such as Toll-like receptor 4 (TLR4), cause chronic inflammation through prolonged activation by various endogenous ligands, including fatty acids and its metabolites. Gangliosides and other glycosphingolipids are important metabolites of fatty acids and saccharides. GM3, the simplest ganglioside comprising α2,3-sialyllactose, is expressed in insulin-sensitive peripheral tissues such as liver and adipose tissue, and furthermore secreted abundantly into serum. It has been shown that GM3 regulates the signal transduction of insulin receptor in adipose tissue as a component of membrane microdomains, and elevation in GM3 level causes insulin resistance. However, the homeostatic and pathophysiological functions of extracellularly secreted GM3 are poorly understood. We recently reported that GM3 species with differing fatty acid structures act as pro- and anti-inflammatory endogenous TLR4 ligands. GM3 with very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA strongly enhanced TLR4 activation. Conversely, GM3 with long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA inhibited TLR4 activation, counteracting the VLCFA species. GM3 interacted with the extracellular complex of TLR4 and promoted dimerization/oligomerization. In obesity and metabolic disorders, VLCFA species were increased in serum and adipose tissue, whereas LCFA species was relatively decreased; their imbalances were correlated to disease progression. Our findings suggest that GM3 species are disease-related endogenous TLR4 ligands, and "glycosphingolipid sensing" by TLR4 controls the homeostatic and pathological roles of innate immune signaling.

Topics: Fatty Acids; G(M3) Ganglioside; Gene Expression Regulation; Homeostasis; Humans; Immunity, Innate; Inflammation; Ligands; Metabolic Diseases; Obesity; Receptor, Insulin; Signal Transduction; Toll-Like Receptor 4

Topics: Animals; Cats; ErbB Receptors; G(M3) Ganglioside; Gangliosides; Glycosphingolipids; Inflammation; Integrins; Neurons; Protein-Tyrosine Kinases; Psychosine; Rabbits; Signal Transduction; Sphingosine

Gangliosides are expressed on plasma membranes throughout the body and enriched in the nervous system. A critical role for complex a- and b-series gangliosides in central and peripheral nervous system ageing has been established through transgenic manipulation of enzymes in ganglioside biosynthesis. Disrupting GalNAc-transferase (GalNAc-T), thus eliminating all a- and b-series complex gangliosides (with consequent over-expression of GM3 and GD3) leads to an age-dependent neurodegeneration. Mice that express only GM3 ganglioside (double knockout produced by crossing GalNAc-T

Topics: Animals; Axons; G(M3) Ganglioside; Gangliosides; Genes, Lethal; Heredodegenerative Disorders, Nervous System; Inflammation; Membrane Microdomains; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; N-Acetylgalactosaminyltransferases; Neurons; Phenotype; Polypeptide N-acetylgalactosaminyltransferase; Ranvier's Nodes; Sialyltransferases; Survival Analysis

The association between central obesity and insulin resistance reflects the properties of visceral adipose tissue. Our aim was to gain further insight into this association by analysing the lipid composition of subcutaneous and omental adipose tissue in obese women with and without insulin resistance.. Subcutaneous and omental adipose tissue and serum were obtained from 29 obese non-diabetic women, 13 of whom were hyperinsulinemic. Histology, lipid and gene profiling were performed.. In omental adipose tissue of obese, insulin-resistant women, adipocyte hypertrophy and macrophage infiltration were accompanied by an increase in GM3 ganglioside and its synthesis enzyme ST3GAL5; in addition, phosphatidylethanolamine (PE) lipids were increased and their degradation enzyme, phosphatidylethanolamine methyl transferase (PEMT), decreased. ST3GAL5 was expressed predominantly in adipose stromovascular cells and PEMT in adipocytes. Insulin resistance was also associated with an increase in PE lipids in serum.. The relevance of these findings to insulin resistance in humans is supported by published mouse studies, in which adipocyte GM3 ganglioside, increased by the inflammatory cytokine tumour necrosis factor-α, impaired insulin action and PEMT was required for adipocyte lipid storage. Thus in visceral adipose tissue of obese humans, an increase in GM3 ganglioside secondary to inflammation may contribute to insulin resistance and a decrease in PEMT may be a compensatory response to adipocyte hypertrophy.

Topics: Adipocytes; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; G(M3) Ganglioside; High-Throughput Nucleotide Sequencing; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Lipids; Middle Aged; Obesity; Phosphatidylethanolamines; Tumor Necrosis Factor-alpha

Vascular endothelial growth factor (VEGF) is well known as a significant angiogenic factor, and also functions as a proinflammatory cytokine, which induces adhesion of leukocyte to endothelial cells in inflammation reaction. In this study, we show that ganglioside GM3 inhibits the VEGF-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) through activation of nuclear factor-κB (NF-κB) via protein kinase B (AKT) signaling in human umbilical vein endothelial cells (HUVECs), relating with leukocyte recruitment to endothelial cells under inflammatory conditions. In addition, ganglioside GM3 significantly reduced the monocyte adhesion to HUVECs as determined by the monolayer cell adhesion assay. Furthermore, in VEGF-injected mice for the inflammatory condition, ganglioside GM3 markedly decreased the expression of ICAM-1 and VCAM-1 in vein tissues. These results suggest that ganglioside GM3 has an anti-inflammatory role by suppressing the expression of inflammatory-related molecules during in vitro and in vivo inflammation.

Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Cytokines; Endothelial Cells; Female; G(M3) Ganglioside; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred BALB C; Monocytes; Signal Transduction; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A