Abstract 1249 Mechanisms and consequences of lipid accumulation in necroptosis

Necroptosis is a type of programmed cell death which is characterized by membrane permeabilization and is known to be associated with strong inflammatory response due to the release of intracellular components based on compromised membrane integrity. Necroptosis is accompanied by key lipid and membrane remodeling and this process is yet to be elucidated. Given this critical role of membranes during necroptosis, little research has focused on understanding the roles of lipids in the membrane-related changes during this process. To identify novel lipid players of necroptosis, we employed untargeted lipidomics and showed that saturated very long chain fatty acids (VLCFAs) accumulated via activated biosynthesis in necroptosis. Depleting the levels of VLCFAs resulted in reduced necroptotic cell death and membrane permeabilization whereas increasing VLCFA levels induced membrane permeabilization, showing that VLCFAs are functionally involved in necroptosis. In this talk, I will discuss the biochemical mechanisms that result in the accumulation of lipids and the functional consequences of these accumulations in this process. Specifically, I will present recent studies from our lab on the mechanisms of fatty acylation events by VCLFAs that contribute to the membrane permeabilization during necroptosis and the sterol-regulatory element binding protein mediated lipid accumulation in this process. Broadly, the talk will focus on new mechanisms of lipid accumulation and function in cell death.