Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity.

The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyl-sn-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain-dependent lipotoxic cell death pathway is phylogenetically conserved.

Citation

Patrick Rockenfeller, Martin Smolnig, Jutta Diessl, Mina Bashir, Vera Schmiedhofer, Oskar Knittelfelder, Julia Ring, Joakim Franz, Ines Foessl, Muhammad J Khan, René Rost, Wolfgang F Graier, Guido Kroemer, Andreas Zimmermann, Didac Carmona-Gutierrez, Tobias Eisenberg, Sabrina Büttner, Stephan J Sigrist, Ronald P Kühnlein, Sepp D Kohlwein, Campbell W Gourlay, Frank Madeo. Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity. Cell death and differentiation. 2018 Mar;25(4):767-783

Mesh Tags

Substances

PMID: 29230001

search → result