Ruggles KV~Sturley SL, 2014

Pubmed ID 24273168
Title A functional, genome-wide evaluation of liposensitive yeast identifies the "ARE2 required for viability" (ARV1) gene product as a major component of eukaryotic fatty acid resistance.
Authors Kelly V Ruggles, Jeanne Garbarino, Ying Liu, James Moon, Kerry Schneider, Annette Henneberry, Jeff Billheimer, John S Millar, Dawn Marchadier, Mark A Valasek, Aidan Joblin-Mills, Sonia Gulati, Andrew B Munkacsi, Joyce J Repa, Dan Rader, Stephen L Sturley
Abstract The toxic subcellular accumulation of lipids predisposes several human metabolic syndromes, including obesity, type 2 diabetes, and some forms of neurodegeneration. To identify pathways that prevent lipid-induced cell death, we performed a genome-wide fatty acid sensitivity screen in Saccharomyces cerevisiae. We identified 167 yeast mutants as sensitive to 0.5 mm palmitoleate, 45% of which define pathways that were conserved in humans. 63 lesions also impacted the status of the lipid droplet; however, this was not correlated to the degree of fatty acid sensitivity. The most liposensitive yeast strain arose due to deletion of the "ARE2 required for viability" (ARV1) gene, encoding an evolutionarily conserved, potential lipid transporter that localizes to the endoplasmic reticulum membrane. Down-regulation of mammalian ARV1 in MIN6 pancreatic β-cells or HEK293 cells resulted in decreased neutral lipid synthesis, increased fatty acid sensitivity, and lipoapoptosis. Conversely, elevated expression of human ARV1 in HEK293 cells or mouse liver significantly increased triglyceride mass and lipid droplet number. The ARV1-induced hepatic triglyceride accumulation was accompanied by up-regulation of DGAT1, a triglyceride synthesis gene, and the fatty acid transporter, CD36. Furthermore, ARV1 was identified as a transcriptional of the protein peroxisome proliferator-activated receptor α (PPARα), a key regulator of lipid homeostasis whose transcriptional targets include DGAT1 and CD36. These results implicate ARV1 as a protective factor in lipotoxic diseases due to modulation of fatty acid metabolism. In conclusion, a lipotoxicity-based genetic screen in a model microorganism has identified 75 human genes that may play key roles in neutral lipid metabolism and disease.
Citation J. Biol. Chem. 2014; 289:4417-31

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Papers Phenotype Conditions Collection Tested mutants Data Details
Ruggles KV~Sturley SL, 2014 growth (colony size) palmitoleate [0.5 mM] hap alpha ~4,800 Quantitative only for hits

Curation history

Data

Sept. 20, 2017 Data to request.
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Tested strains

Sept. 20, 2017 Tested strains to request.
Sept. 21, 2017 Tested strains requested.
Jan. 20, 2018 Tested strains requested.
April 3, 2018 Tested strains abandoned.