GSE133939
Saturated fatty acids promotes ß-cell toxicity by disabling intracellular lipid droplet formation through S-acylation of FIT2
Palm and coconut oils are linked to cardiovascular disease and diabetes because of their high saturated fatty acid (SFA) content but exactly how exogenous SFAs, but not unsaturated fatty acids (UFA), are toxic to cells remains unknown. In insulin-producing, ß-cells of the Islets of Langerhans, loss of which exacerbates diabetes, we found that SFAs but not UFAs were toxic because they disable a highly conserved lipid droplet biogenesis machinery. We show that palmitate (a major SFA of these oils), but not palmitoleic or oleic, S-acylates the highly conserved ER-resident FITM2 protein, required for lipid coalescence and droplet budding from the ER. The S-acylation marks FITM2 for ubiquitination and proteosomal degradation, leaving SFAs within the ER instead safe sequestration within lipid droplets. ER-stress ensues with rapid induction of ER stress leading to ß-cell apoptosis. Specific deletion of FITM2 in ß-cells disrupts calcium signaling and key ß-cell TFs and exacerbates high fat diet-induced ER stress and diabetes. Rescue by overexpression ameliorates ER-stress and ß-cell apoptosis thus demonstrating an important link between lipid species and cell ability to sequester them away from the ER in the form of lipid droplets. Overall design: Pancreatic islet mRNA profiles of 12 week old wild type (WT) and ß-cell specific FIT2 knockout (ß-FIT2KO, KO) mice were generated with the Illumina NextSeq, in quintuplicate