2019 Volume 22 Pages 1-7
Innate immune signaling via endogenous TLR4 ligands plays important roles in pathogenesis of metabolic disorders. Recently, we found that ganglioside GM3, one of glycosphingopilids, acts as an endogenous TLR4 modulator. GM3 ganglioside in human serum is comprised of a variety of fatty acids including long-chain (LCFA), very long-chain (VLCFA), and those with modifications such asω-9 desaturation and α-hydroxylation. VLCFA GM3 synergistically and selectively enhanced TLR4 activation by LPS and HMGB1, and in contrast, LCFA- and unsaturated VLCFA GM3 inhibited TLR4 activation. In metabolic disorders, serum VLCFA GM3 increased, while LCFA GM3 decreased, indicating the proinflammatory shift of GM3 species. VLCFA-and α-hydroxyl GM3 increased in the adipose tissue of obese mice, and the increase was attenuated in TLR4-mutant mice, implying that TLR4 signaling itself is involved in production of VLCFA GM3. Our findings suggest that serum GM3 species modulate TLR4 signaling, and the increase of VLCFA GM3 is a risk factor for TLR4-mediated disease progression.
