Homeostatic and pathogenic roles of the GM3 ganglioside

• Published in: The FEBS journal 2022-09, Vol.289 (17), p.5152-5165
• Main Authors: Inokuchi, Jin‐ichi, Kanoh, Hirotaka, Inamori, Kei‐ichiro, Nagafuku, Masakazu, Nitta, Takahiro, Fukase, Koichi
• Format: Article
• Language: English
• Subjects: adipocytes; Adipogenesis; Adipose tissue; Biosynthesis; Chains; Cholesterol; cholesterol transport; chronic inflammation; Cloning; Energy balance; Ganglioside GM3; Gangliosides; GM3 ganglioside; Homeostasis; Hypothalamus; Immune response; Inflammation; Innate immunity; Insulin; Insulin resistance; Intestine; Lactosylceramide a-2,3-sialyltransferase; Leptin; leptin resistance; Macrophages; Metabolic disorders; metabolic syndrome; Modulators; NPC1L1; obesity; Physiological effects; Physiology; Species; TLR4; TLR4 protein; Toll-like receptors
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16076

Two decades ago, we achieved molecular cloning of ganglioside GM3 synthase (GM3S; ST3GAL5), the enzyme responsible for initiating biosynthesis of complex gangliosides. The efforts of our research group since then have been focused on clarifying the physiological and pathological roles of gangliosides, particularly GM3. This review summarizes our long‐term studies on the roles of GM3 in insulin resistance and adipogenesis in adipose tissues, cholesterol uptake in intestine, and leptin resistance in hypothalamus. We hypothesized that GM3 plays a role in innate immune function of macrophages and demonstrated that molecular species of GM3 with differing acyl‐chain structures and modifications functioned as pro‐ and anti‐inflammatory endogenous Toll‐like receptor 4 (TLR4) modulators in macrophages. Very‐long‐chain and α‐hydroxy GM3 species enhanced TLR4 activation, whereas long‐chain and unsaturated GM3 species counteracted this effect. Lipidomic analyses of serum and adipose tissues revealed that imbalances between such pro‐ and anti‐inflammatory GM3 species promoted progression of metabolic disorders. GM3 thus functions as a physiological regulatory factor controlling the balance between homeostatic and pathological states. Ongoing studies based on these findings will clarify the mechanisms underlying ganglioside‐dependent control of energy homeostasis and innate immune responses. We here discuss the pathophysiological significance of GM3 molecular species. Increase of very long‐chain (VLCA) GM3 species occurs in obesity and plays a pathogenic role in the early stage of metabolic disorders by synergistically activating TLR4 inflammatory signaling with PAMPs and DAMPs. Furthermore, abundance of α‐hydroxy VLCFA‐GM3 (h24:0) shows correlation with BMI and abdominal circumference and is also correlated with indicators of insulin resistance and chronic inflammation.