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  3. Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids

Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids

  • Mol Cell. 2019 Apr 4;74(1):32-44.e8. doi: 10.1016/j.molcel.2019.01.036.
Manuele Piccolis 1,  Laura M Bond 1,  Martin Kampmann 2,  Pamela Pulimeno 1,  Chandramohan Chitraju 1,  Christina B K Jayson 1,  Laura P Vaites 3,  Sebastian Boland 1,  Zon Weng Lai 1,  Katlyn R Gabriel 4,  Shane D Elliott 4,  Joao A Paulo 3,  J Wade Harper 3,  Jonathan S Weissman 2,  Tobias C Walther 5,  Robert V Farese Jr 6
Affiliations

Affiliations

  • 1 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research and Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • 5 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: [email protected].
  • 6 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].
PMID: 30846318 DOI: 10.1016/j.molcel.2019.01.036
Abstract

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.

Keywords

Moyamoya disease; glycerolipid; lipotoxicity; palmitate; saturated fatty acid.

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