Targeted lipidomics reveals a novel role for glucosylceramides in glucose response

iso‐Fatty Acid Metabolism in Caenorhabditis elegans’ Ceramide Biosynthesis

“…Ceramide ( 18 ) profiling of the Caenorhabditis elegans lipidome was performed by targeted HPLC‐ESI‐(+)‐HR‐MS analysis for previously described components ( Figure 1 ,a and 1,b ) [16,19] all of which were also detected upon ESI‐(+)‐HR‐MS e screening ( Figure 1 ,c ) for the characteristic sphingosine‐derived fragment ion at m/z 250.2529 [C 17 H 32 N] + as a highly sensitive marker signal ( Scheme 1 ,d ) [16,29,30,49] . Isomeric structures were assigned based on the incorporation of branched‐chain amino acids (BCAA).…”

“…Ceramide (18) profiling of the Caenorhabditis elegans lipidome was performed by targeted HPLC-ESI-(+)-HR-MS analysis for previously described components (Figure 1,a and 1,b) [16,19] all of which were also detected upon ESI-(+)-HR-MS e screening (Figure 1,c) for the characteristic sphingosine-derived fragment ion at m/z 250.2529 [C 17 H 32 N] + as a highly sensitive marker signal (Scheme 1,d). [16,29,30,49] Isomeric structures were assigned based on the incorporation of branchedchain amino acids (BCAA). A total of 48 ceramides 18 were identified, which constitute a homologous series characterized by a conserved d17 : 1iso sphingosine (17) backbone that is N-acylated with straight and isobranched acyl and 2-hydroxy-acyl moieties ranging from 16 to 27 carbons (Figure 1,a -1,c, Tables S1 and S2).…”

“…Similar glycosyl ceramides were identified in the parasitic Ascaris suum [22,23] . Recent research has demonstrated that these glucosylceramides (GlcCer d17 : 1iso, 19 ) promote postembryonic development, [24,25] foraging behavior, [26] lifespan, [27] and longevity, [28] and mediate survival of developmental arrest, [29] glucose response, [30] intestinal apical membrane polarity, [31] oocyte formation and early embryonic cell division [32] through «Target of Rapamycin Complex 1» (TORC1) signaling, which functions in nutrient sensing [33] …”

“…[19 -21] Similar glycosyl ceramides were identified in the parasitic Ascaris suum. [22,23] Recent research has demonstrated that these glucosylceramides (GlcCer d17 : 1iso, 19) promote postembryonic development, [24,25] foraging behavior, [26] lifespan, [27] and longevity, [28] and mediate survival of developmental arrest, [29] glucose response, [30] intestinal apical membrane polarity, [31] oocyte formation and early embryonic cell division [32] through «Target of Rapamycin Complex 1» (TORC1) signaling, which functions in nutrient sensing. [33] Biosynthesis of the characteristic d17 : 1iso sphingosine building block 17 in C. elegans involves condensation of C15iso-CoA (14a) with L-serine (2; Scheme 1,c) and depends on two branched-chain fatty acids (BCFAs), C15iso (14b) and C17iso (15b) that are essential for C. elegans growth and development, [34 -36] as well as ER homeostasis and lipid droplet growth.…”

Defining the glucosylceramide population of C. elegans

“…In C. elegans , there are three ceramide synthases, HYL-1, HYL-2, and LAGR-1 that add a fatty acid to the sphingoid backbone via an amide linkage to form ceramides ( Menuz et al, 2009 ; Mosbech et al, 2013 ). The fatty acids can range in chain length from 18 to 27 carbons with 0 or 1 double bond, and the specific ceramide synthase used confers chain specificity to sphingolipids ( Cheng et al, 2019 ; Hänel et al, 2019 ; Xatse et al, 2023 ). For example, the ceramide synthase, HYL-1, adds fatty acyl chains of 24–26 carbons, whiles HYL-2 adds 20–22 carbon fatty acyl chains to the sphingoid backbone ( Mosbech et al, 2013 ).…”