Sterol and diacylglycerol acyltransferase deficiency triggers fatty acid-mediated cell death. Academic Article uri icon

Overview

abstract

  • Deletion of the acyltransferases responsible for triglyceride and steryl ester synthesis in Saccharomyces cerevisiae serves as a genetic model of diseases where lipid overload is a component. The yeast mutants lack detectable neutral lipids and cytoplasmic lipid droplets and are strikingly sensitive to unsaturated fatty acids. Expression of human diacylglycerol acyltransferase 2 in the yeast mutants was sufficient to reverse these phenotypes. Similar to mammalian cells, fatty acid-mediated death in yeast is apoptotic and presaged by transcriptional induction of stress-response pathways, elevated oxidative stress, and activation of the unfolded protein response. To identify pathways that protect cells from lipid excess, we performed genetic interaction and transcriptional profiling screens with the yeast acyltransferase mutants. We thus identified diacylglycerol kinase-mediated phosphatidic acid biosynthesis and production of phosphatidylcholine via methylation of phosphatidylethanolamine as modifiers of lipotoxicity. Accordingly, the combined ablation of phospholipid and triglyceride biosynthesis increased sensitivity to saturated fatty acids. Similarly, normal sphingolipid biosynthesis and vesicular transport were required for optimal growth upon denudation of triglyceride biosynthesis and also mediated resistance to exogenous fatty acids. In metazoans, many of these processes are implicated in insulin secretion thus linking lipotoxicity with early aspects of pancreatic beta-cell dysfunction, diabetes, and the metabolic syndrome.

publication date

  • August 18, 2009

Research

keywords

  • Diacylglycerol O-Acyltransferase
  • Fatty Acids
  • Saccharomyces cerevisiae
  • Sterols

Identity

PubMed Central ID

  • PMC2781500

Scopus Document Identifier

  • 71449099158

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.050443

PubMed ID

  • 19690167

Additional Document Info

volume

  • 284

issue

  • 45