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

Rockenfeller, P., Smolnig, M., Diessl, J., Bashir, M., Schmiedhofer, V., Knittelfelder, O., et al. (2018). Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: A model for lipotoxicity. Cell Death and Differentiation, 25(4), 765-781. doi:10.1038/s41418-017-0014-2.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-8DED-F Version Permalink: http://hdl.handle.net/21.11116/0000-0001-4A05-7
Genre: Journal Article

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 Creators:
Rockenfeller, P., Author
Smolnig, M., Author
Diessl, J., Author
Bashir, M., Author
Schmiedhofer, V., Author
Knittelfelder, O., Author
Ring, J., Author
Franz, J., Author
Foessl, I., Author
Khan, M. J., Author
Rost, R., Author
Graier, W. F., Author
Kroemer, G., Author
Zimmermann, A., Author
Carmona-Gutierrez, D., Author
Eisenberg, T., Author
Büttner, S., Author
Sigrist, S. J., Author
Kühnlein, R. P.1, Author              
Kohlwein, S. D., Author
Gourlay, C. W., AuthorMadeo, F., Author more..
Affiliations:
1Research Group of Molecular Physiology, MPI for biophysical chemistry, Max Planck Society, ou_578592              

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Free keywords: Cell biology; Fatty acids; Lipidomics; Membrane lipids; Molecular biology
 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.

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Language(s): eng - English
 Dates: 2017-12-112018-04
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41418-017-0014-2
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Title: Cell Death and Differentiation
Source Genre: Journal
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Pages: - Volume / Issue: 25 (4) Sequence Number: - Start / End Page: 765 - 781 Identifier: -