Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Rockenfeller, P; Smolnig, M; Diessl, J; Bashir, M; Schmiedhofer, V; Knittelfelder, O; Ring, J; Franz, J; Foessl, I; Khan, MJ; Rost, R; Graier, WF; Kroemer, G; Zimmermann, A; Carmona-Gutierrez, D; Eisenberg, T; Büttner, S; Sigrist, SJ; Kühnlein, RP; Kohlwein, SD; Gourlay, CW; Madeo, F.
Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity.
Cell Death Differ. 2018; 25(4):767-783
Doi: 10.1038/s41418-017-0014-2
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- Leading authors Med Uni Graz
- Rockenfeller Patrick
- Co-authors Med Uni Graz
- Bashir Mina
- Eisenberg Tobias
- Fößl Ines
- Franz Joakim
- Graier Wolfgang
- Khan Muhammad Jadoon
- Rost René
- Zimmermann Andreas
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Diglycerides - pharmacology
- Drosophila melanogaster - administration & dosage
- Endothelial Cells - metabolism, pathology
- Humans - administration & dosage
- Models, Biological - administration & dosage
- Necrosis - administration & dosage
- Palmitic Acid - pharmacology
- Repressor Proteins - genetics, metabolism
- Saccharomyces cerevisiae - genetics, metabolism
- Saccharomyces cerevisiae Proteins - genetics, metabolism
- Signal Transduction - drug effects