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.
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.
authors.affiliation: From the Institute of Human Nutrition and.
authors.forename: Kelly V
authors.initials: KV
authors.lastname: Ruggles
authors.forename: Jeanne
authors.initials: J
authors.lastname: Garbarino
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.forename: Kerry
authors.initials: K
authors.lastname: Schneider
authors.forename: Annette
authors.initials: A
authors.lastname: Henneberry
authors.forename: Jeff
authors.initials: J
authors.lastname: Billheimer
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Dawn
authors.initials: D
authors.lastname: Marchadier
authors.forename: Mark A
authors.initials: MA
authors.lastname: Valasek
authors.forename: Aidan
authors.initials: A
authors.lastname: Joblin-Mills
authors.forename: Sonia
authors.initials: S
authors.lastname: Gulati
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Munkacsi
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.forename: Dan
authors.initials: D
authors.lastname: Rader
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sturley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
chemical_list: C467736:ARV1 protein, S cerevisiae; C553399:ARV1 protein, human; C553398:ARV1 protein, mouse; D018955:CD36 Antigens; D002352:Carrier Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; D047493:PPAR alpha; D029701:Saccharomyces cerevisiae Proteins; D014280:Triglycerides; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: Fatty Acid; Lipid Droplets; Lipid Metabolism; Lipotoxicity; Triglyceride; Yeast Genetics