title: Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids.
abstract: The degree of fatty acid unsaturation in membrane phospholipids affects many membrane-associated functions and can be influenced by dietary consumption of fatty acids such as saturated fatty acids and polyunsaturated fatty acids (PUFAs). Cells must adapt to changes in composition of membrane fatty acids by regulating lipid-metabolizing enzymes. In this study, we investigated how cells respond to loading with excess PUFAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. A lipidomics analysis revealed that dipalmitoylphosphatidylcholine (DPPC) was increased after the production of PUFA-containing phospholipids in cells loaded with PUFAs. An RNA interference screen of lipid-metabolizing enzymes revealed that lysophosphatidylcholine acyltransferase 1 (LPCAT1) was involved in the DPPC production. Moreover, LPCAT1 knockdown markedly enhanced the cytotoxicity induced by excess PUFAs. PUFA-induced cytotoxicity was dependent on caspase and unfolded protein response (UPR) sensor proteins inositol requiring 1α and protein kinase R-like endoplasmic reticulum kinase, suggesting that excess PUFAs trigger UPR-mediated apoptosis. In murine retina, in which PUFAs are highly enriched, DPPC was produced along with increase of PUFA-containing phospholipids. In LPCAT1 knockout mice, DPPC level was reduced and UPR was activated in the retina. Our results provide insight into understanding of the retinal degeneration seen in rd11 mice that lack LPCAT1.-Akagi, S., Kono, N., Ariyama, H., Shindou, H., Shimizu, T., Arai, H. Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids.
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Akagi
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan nozomu@mol.f.u-tokyo.ac.jp.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kono
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ariyama
authors.affiliation: Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan Japan Agency for Medical Research and Development-Core Research for Evolutionary Science and Technology (AMED-CREST), Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shindou
authors.affiliation: Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan Japan Agency for Medical Research and Development-Core Research for Evolutionary Science and Technology (AMED-CREST), Tokyo, Japan harai@mol.f.u-tokyo.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D015060:1,2-Dipalmitoylphosphatidylcholine; D015118:Eicosapentaenoic Acid; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse
keywords: fatty acid metabolism; membrane phospholipid homeostasis; phospholipid metabolism