Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids
| Autor: | J. Wade Harper, Pamela Pulimeno, Shane D. Elliott, Laura Pontano Vaites, Zon Weng Lai, Tobias C. Walther, Robert V. Farese, Christina B. K. Jayson, Joao A. Paulo, Katlyn R. Gabriel, Sebastian Boland, Jonathan S. Weissman, Chandramohan Chitraju, Laura M. Bond, Manuele Piccolis, Martin Kampmann |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
endoplasmic-reticulum stress
purification Ubiquitin-Protein Ligases Palmitic Acid Biology Endoplasmic Reticulum Article Gene Expression Regulation Enzymologic Glycerides Transcriptome 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Humans Molecular Biology 030304 developmental biology Adenosine Triphosphatases 0303 health sciences phosphorylation Endoplasmic reticulum hepatic steatosis apoptosis Cell Biology unfolded protein response Hep G2 Cells Lipidome Endoplasmic Reticulum Stress Lipid Metabolism Cell biology Ubiquitin ligase rnf213 Lipotoxicity Saturated fatty acid biology.protein Unfolded protein response identification palmitate diacylglycerol acyltransferase K562 Cells Sterol Regulatory Element Binding Protein 1 030217 neurology & neurosurgery Acyltransferases HeLa Cells |
| Zdroj: | Mol Cell |
| Popis: | Excessive levels of saturated fatty acids are toxic to cells, although the basis for this lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating lipotoxicity. Among previously unknown genetic modifiers of lipotoxicity, depletion of RNF213, a putative ubiquitin ligase mutated in Moyamoya vascular disease, protected cells from lipotoxicity. On a broader level, integration of our comprehensive datasets revealed that changes in di-saturated glycerolipids, but not other lipid classes, are central to lipotoxicity in this model. Consistent with this, inhibition of ER-localized glycerol-3-phosphate acyltransferase activity protected from all aspects of lipotoxicity. Identification of genes modulating the response to saturated fatty acids may reveal novel therapeutic strategies for treating metabolic diseases linked to lipotoxicity. |
| Databáze: | OpenAIRE |
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