title: Sterol and diacylglycerol acyltransferase deficiency triggers fatty acid-mediated cell death.
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.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Garbarino
authors.forename: Mahajabeen
authors.initials: M
authors.lastname: Padamsee
authors.forename: Lisa
authors.initials: L
authors.lastname: Wilcox
authors.forename: Peter M
authors.initials: PM
authors.lastname: Oelkers
authors.forename: Diana
authors.initials: D
authors.lastname: D'Ambrosio
authors.forename: Kelly V
authors.initials: KV
authors.lastname: Ruggles
authors.forename: Nicole
authors.initials: N
authors.lastname: Ramsey
authors.forename: Omar
authors.initials: O
authors.lastname: Jabado
authors.forename: Aaron
authors.initials: A
authors.lastname: Turkish
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sturley
mesh_terms: D016923:Cell Death / Q000187:drug effects; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism / Q000633:toxicity*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D050296:Microbial Viability; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013261:Sterols / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C494880:DGA1 protein, S cerevisiae; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
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