Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids
Open accessAbstract
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.
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Oligodendrocytes show sensitivity to changes in lipoapoptosis modulating genes Scd1 and Insig1.
“We also observed sensitivity of oligodendrocytes to changes in lipoapoptosis modulating genes Scd1 and Insig1 (Extended Data Figure 8b-c)16,17.”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [16]
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Neurotoxic reactive astrocytes induce cell death via saturated lipids
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- Authors
- Piccolis, M., Bond, L. M., Kampmann, M., Pulimeno, P., Chitraju, C., Jayson, C. B. K., Vaites, L. P., Boland, S., Lai, Z. W., Gabriel, K. R., Elliott, S. D., Paulo, J. A., Harper, J. W., Weissman, J. S., Walther, T. C., & Farese, R. V.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- Corresponding author
- Walther, Tobias C.
- Farese, Robert V.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 74
- Issue
- 1
- Pages
- 32-44.e8
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC7696670
- OpenAlex
- W2918938634
- Cited by
- 269
- References
- 63
- Citations by year
- 2026: 20 · 2025: 38 · 2024: 47 · 2023: 34 · 2022: 34 · 2021: 53 · 2020: 29 · 2019: 14
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Swiss National Foundation (K99/R00 CA181494)
- National Science Foundation (DGE1144152)
- Department of Defense (K01 DK098285, R01 DK101579, R37 NS083524, R01NS110395)
- Mathers Foundation
- Pfizer
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- lipotoxicity, saturated fatty acids, palmitate, endoplasmic reticulum stress response, transcriptional stress response, RNF213, ubiquitin ligase, glycerol-3-phosphate acyltransferase, genetic modifiers, leukemia cells, lipidome, transcriptome, metabolic disorders
- MeSH terms
- Acyltransferases, Adenosine Triphosphatases, Endoplasmic Reticulum, Glycerides, HeLa Cells, Humans, Gene Expression Regulation, Enzymologic, Palmitic Acid, K562 Cells, Ubiquitin-Protein Ligases, Lipid Metabolism, Sterol Regulatory Element Binding Protein 1, Hep G2 Cells, Transcriptome, Endoplasmic Reticulum Stress
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