A Dying Cell’s Last Hope: β-Oxidation of Lipid Droplets as a Method of Prolonging Cell Death

Paper: Cell survival during Complete Nutrient Deprivation Depends on Lipid Droplet-fueled β-oxidation of Fatty Acids.

http://www.jbc.org/content/288/39/27777.full.pdf+html?sid=958a2e65-ca82-45c9-91e3-561a3cd2278e

LN18 cells were prelabeled overnight with [3H]palmitate prior to their treatment with DMEM (gray bar) or KH without glucose in the absence (solid symbols) or presence of 1 M py-2 (open symbols) or 30 M EX (open bar). -Oxidation was monitored after the generation of [3H]water. The inset shows increased expression of CPT1 after 16 h of starvation. B and C, [3H]palmitateprelabeledCHO( B) or HeLa (C) cells were treated for 4 h with culture medium (gray bar) orKHwithout glucose in the absence (solid bar) or presence of 1Mpy-2 (open bar). -Oxidation was defined as EX-sensitive production of [3H]water. Results are means  S.E. (error bars) of an experiment carried out with determinations in quadruplicate and are representative of four (A) or three (B and C) independent experiments with similar outcome. *, significantly different from KH without glucose.
Nutrient deprivation induces beta-oxidation that requires LD biogenesis. LN18 cells were prelabeled overnight with [3H]palmitate prior to their treatment with or without glucose. Oxidation was monitored after the generation of [3H]water.  [3H]palmitateprelabeledCHO or HeLa (C) cells were treated for 4 h with culture medium or without glucose
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.

2 Replies to “A Dying Cell’s Last Hope: β-Oxidation of Lipid Droplets as a Method of Prolonging Cell Death”

  1. You mentioned that CHO, LN18 human glioblastoma, HeLa, and rat astrocyte cell lines were used, and that potential implications include anti-tumor therapies. Were differential degrees of cell protection observed across cell types?

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