Pathophysiological Significance of GM3 Ganglioside Molecular Species With a Particular Attention to the Metabolic Syndrome Focusing on Toll-Like Receptor 4 Binding

Abstract

GM3 ganglioside, the first molecule in ganglioside family biosynthesis, is formed by transfer of sialic acid to lactosylceramide. Several dozen GM3 molecular species exist, based on diversity of ceramide structures. Among ceramide structures composed of sphingosine and fatty acids, there is a great diversity resulting from different combinations of chain length, hydroxylation, and unsaturation of fatty acid chains. Expression patterns of GM3 species in serum vary during pathogenesis of metabolic syndrome. Physiological activity of each species, and significance of the variability, are poorly understood. Our studies revealed that GM3 species with differing fatty acid structures act as pro- or anti-inflammatory endogenous Toll-like receptor 4 (TLR4) ligands. Very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA GM3 variants strongly enhanced TLR4 activation. In contrast, long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA GM3 variants suppressed TLR4 activation. GM3 interacted with extracellular TLR4/myeloid differentiation factor 2 (MD-2) complex, thereby promoting dimerization/oligomerization. In obesity and metabolic syndrome, VLCFA-variant GM3 species were elevated in serum and adipose tissue, whereas LCFA-variant species were reduced, and such imbalances were correlated with disease progression. Our findings summarized in this review demonstrate that GM3 molecular species are disease-related endogenous TLR4 ligands and modulate homeostatic and pathogenic innate immune responses.

Perioperative changes in ganglioside monosialodihexosylganglioside (GM3) molecular species for benign prostatic hyperplasia: a preliminary report

“…Long-chain GM3 variations (16:0 and 18:0) have been used to inhibit inflammatory cytokine production in cases of chronic inflammatory disease ( 10 ). GM3 species have a key role in regulating inflammatory processes ( 15 , 16 ). GM3 species are correlated with insulin resistance, hypercholesterolemia, and the mediation of pro- or anti-inflammatory mechanisms by influencing toll-like receptors and consequently the production of pro-inflammatory cytokines ( 10 , 16 ).…”

Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids

“…For cells to have the very-long-chain fatty acids identified in the ceramide components of GM3, cellular very-long-chain fatty acid (VLCFA) elongases (ELOVL1-7) had to catalyze the elongation of the typical fatty acids synthesized [ 128 ]. In the early stages of metabolic syndrome, there is an increase in proinflammatory VLCFAs (22:0, 23:0, 24:0, h24:0) in serum and adipose tissue [ 129 ]. In severe obesity and metabolic syndrome, macrophage expression of VLCFAs decreases due to steroid regulatory element-binding protein SREBP1-induced reprograming of lipid synthesis [ 130 ].…”

“…The effect of this change on GG function remains unknown. Human milk [133] Primarily C24:0,24:1, shorter chains not effective [106], predominantly ≥ C20 [133] d18:1 > d20:1 in human milk [133] Outside-in signaling [106,134]; skin problems, atherosclerosis, mitochondrial disfunction [135] GM3 H 1 : adipose, muscle, liver + serum [127,129]; mature outer retina [136] Primarily C18,22,24,24:1 w9 [137] d18:1 [137,138] d20:1 predominant in pyramidal and granular layers of the dentate gyrus [139] Type 2 diabetes, metabolic disease, and innate immune response [127][128][129] GD3 Prevalent in neuronal stem cells [140] Plasma membrane cytoplasm, ER-mitochondria-associated membranes [141] Longer-chain fatty acids > C18:0 in adult human brain [142] d18:1 > d20:1 Enhances proliferation via its roles in signal transduction (for a review, see [143])…”

Glycosphingolipids in Diabetes, Oxidative Stress, and Cardiovascular Disease: Prevention in Experimental Animal Models

“…However, we and others showed that D-PDMP not only inhibited the activity in purified human kidney LacCer synthase and reduced LacCer generation, but also in various organs derived from multiple animal models of cardiovascular disease and T2D [ 16 , 61 ]. The pathophysiological role of GM3 involving toll like receptor-4 binding in adipose tissue in metabolic syndrome has been elegantly shown recently [ 62 ].…”