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. Epub 2019 Mar 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyltransferases / genetics
  • Acyltransferases / metabolism
  • Adenosine Triphosphatases / metabolism
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / genetics
  • Gene Expression Regulation, Enzymologic
  • Glycerides / metabolism*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • K562 Cells
  • Lipid Metabolism / drug effects*
  • Lipid Metabolism / genetics
  • Palmitic Acid / toxicity*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Transcriptome
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Glycerides
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Palmitic Acid
  • Acyltransferases
  • RNF213 protein, human
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases