Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity

Abstract

Innate immune signaling viaTLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear.GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serumGM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels ofVLCFA-GM3 increase significantly in metabolic disorders, whileLCFA-GM3 serum levels decrease. SpecificGM3 species also correlates with disease symptoms.VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked inTLR4-mutant mice. In cultured monocytes,GM3 by itself has no effect onTLR4 activation; however,VLCFA-GM3 synergistically and selectively enhancesTLR4 activation byLPS/HMGB1, whileLCFA-GM3 and unsaturatedVLCFA-GM3 suppressesTLR4 activation.GM3 interacts with the extracellular region ofTLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports thatVLCFA-GM3 andLCFA-GM3 act as agonist and antagonist ofTLR4 activity, respectively, by differentially binding to the hydrophobic pocket ofMD2. Our findings suggest thatVLCFA-GM3 is a risk factor forTLR4-mediated disease progression.