Fig. 10.

Schematic summary of the differential effects of SPL versus SGPP1 on FFA-mediated toxicity in pancreatic beta-cells. In INS1E-ctr cells, PA induces ER stress, mild mitochondrial stress related to the accumulation of proapoptotic ceramides in mitochondria and oxidative stress (H₂O₂ formation mainly in cytoplasm and peroxisomes), while OA is not toxic and stimulates lipid droplets formation. The enhanced S1P cleavage capacity by SPL overexpression accelerates toxic effects of PA and sensitized to OA via potentiation of oxidative and ER stress responses as well as reduction of lipid storage capacity accompanied by a massive accumulation of pro-apoptotic ceramides in mitochondria. SGPP1 overexpression protects against lipotoxicity via upregulation of lipid storage (LD particularly of a bigger size) and decrease in ceramide formation. For details with regard to human beta cells, look in Discussion. ER, endoplasmic reticulum, LD, lipid droplet, ROS, reactive oxygen species, UPR^ER, ER unfolded protein response, UPR^mt, mitochondrial unfolded protein response.