Assembling fats and sugar for cardiac protection

Balligand, Jean-Luc [UCL] Michel, Lauriane [UCL]

(eng) This editorial refers to ‘Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking’, by L. Andersson et al., https://doi.org/10.1093/eurheartj/ehab412. Cardiac myocytes synthesize glucosyl- (and gactosyl-) ceramides from ceramide through glucosyl-ceramide synthase (encoded by Ugcg). As demonstrated from the phenotype of Ugcg–/– mice (right-hand side), these sphingosides are necessary for the internalization and recycling of membrane G-protein-coupled receptors, such as the beta1-adrenergic receptor (Adrb1), to maintain receptor coupling. Ugcg defi- ciency leads to Adrb1 desensitization and loss of cardiac contractile reserve. Ugcg–/– mice also exhibit reduced autophagy (illustrated with a reduced number of autophagosomes). These (and other defects of the endosomal pathway) lead to progressive heart failure and premature death. Cardiac muscle extracts from heart failure patients (left-hand side), however, are enriched in Glc-Cer and Lac-Cer, raising the possibility that these changes represent an adaptation mechanism of the cardiac muscle to stress. Whether these increased sphingosides actually optimize GPCR (including Adrb1) recycling/coupling and/or the endolysosomial/autophagy pathway for improved contractility/cell survival remains hypothetical. Adrb1, adren- ergic receptor, beta-1 subtype; GPCR, G-protein-coupled receptor; Lac-Cer, lactosyl-ceramide; Glc-Cer, glucosyl-ceramide; Ugcg: UDP-glucose ceramide glucosyltransferase. [...]