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

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. [Display omitted] •Treatment of cells with palmitate increases saturated glycerolipids and ER stress•Di-saturated glycerolipids are key to lipotoxicity in this model•Inhibiting ER-localized GPAT enzymes protects cells from lipotoxicity•Depletion of the putative E3 ligase RNF213 protects cells from lipotoxicity Cellular lipotoxicity due to saturated fatty acids causes cell death and is thought to be a root cause of metabolic diseases. Piccolis, Bond, et al. use unbiased analyses to reveal hundreds of genes modulating cellular palmitate lipotoxicity and implicate saturated glycerolipids as a causative factor.