Lipid droplets protect human β cells from lipotoxic-induced stress and cell identity changes

Abstract

AbstractFree fatty acids (FFAs) are often stored in lipid droplet (LD) depots for eventual metabolic and/or synthetic use in many cell types, such a muscle, liver, and fat. In pancreatic islets, overt LD accumulation was detected in humans but not mice. LD buildup in islets was principally observed after roughly 11 years of age, increasing throughout adulthood under physiologic conditions, and also enriched in type 2 diabetes. To obtain insight into the role of LDs in human islet β cell function, the levels of a key LD structural protein, perilipin2 (PLIN2), were manipulated by lentiviral-mediated knock-down (KD) or over-expression (OE) in EndoCβH2-Cre cells, a human cell line with adult islet β-like properties. Glucose stimulated insulin secretion was blunted in PLIN2KD cells and improved in PLIN2OE cells. An unbiased transcriptomic analysis revealed that limiting LD formation induced effectors of endoplasmic reticulum (ER) stress that compromised the expression of critical β cell function and identity genes. These changes were aggravated by exogenous treatment with FFAs toxic to islet β cells, and essentially reversed by PLIN2OE or using the ER stress inhibitor, tauroursodeoxycholic acid. These results strongly suggest that LDs are essential for adult human islet β cell activity by preserving FFA homeostasis.