Paper: Cell survival during Complete Nutrient Deprivation Depends on Lipid Droplet-fueled β-oxidation of Fatty Acids.
A Dying Cell’s Last Hope: β-Oxidation of Lipid Droplets as a Method of Prolonging Cell Death
Exposure to various types of cellular stresses, typically committing the cell to death, results in the synthesis of triacylglycerols (TAGs) that are used to generate lipid droplets (LD) as mediated by Group IVA phopholipase A2 (cPLA2). LD are organelles composed of TAGs and cholesteryl esters that are thought to have a variety of functions, such as supplying metabolic fuels and membrane building blocks as well as acting as transcription factor regulators. The origin and role of the LD generation, however, is not completely understood. Prior research suggests that TAG synthesis is necessary for LD biogenesis and has shown that the presence of LD attenuates cellular stress resulting from the absence of extracellular lipids. Based on this prior research, the authors studied whether the generation of these LD may be a method of generating catabolic fuel for metabolism in a nutrient-deprived environment.
To assess whether LD generation has a prosurvival role to cellular stress, the authors deprived various cell types (CHO, LN18 human glioblastoma, HeLa, or rat astrocytes) of glucose and measured the LD content in the cell in the presence and absence cPLA2 phosphorylation. Down-regulation of cPLA2 was achieved through py-2, a known inhibitor of phosphorylation, or down-regulation of CERK, also involved in the phosphorylation pathway. It was found that LD biogenesis occurred in response to glucose-deprivation, prolonging cell death, and that inhibition of cPLA2 hindered LD formation, accelerating cell death. Following verification of LD biogenesis, the authors investigated the relationship between LD formation and cell survival by using flow cytometry and immunochemistry to measure the differences in LD content between cells pre-loaded with LD before glucose deprivation to those without prior LD exposure and also in cells where β-oxidation of LD is inhibited. When cells are exposed to a nutrient-deprived state, the authors found, through the use of H-labeled lipids, that LD formation is necessary for β-oxidation. Experiments demonstrated that a lack of LD biogenesis and an inhibition of β-oxidation of LD in nutrient-deprived state results in accelerated cell death. The data suggests that in response to complete nutrient-deprivation, cells synthesize TAGs, as mediated through cPLA2, which are packaged into LD to be used for β-oxidation to delay cell death. Since LD biogenesis has been shown to be also associated with other models of cellular stresses and various other pathological conditions, further studies could be used to develop cell-protecting therapies or possible anti-tumor cancer drugs.