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Many meibum lipids contain fatty alcohols (FAls) with chain lengths \u2265C24, but the fatty acyl\u2010CoA reductases (FARs) that produce them remain unclear. Here, using cell\u2010based assays, we found that the two FAR isozymes (FAR1 and FAR2) show different substrate specificities: FAR1 and FAR2 are involved in the production of C16\u2013C18 and \u2265C20 FAls, respectively. Next, we generated\n                    <jats:italic>Far2<\/jats:italic>\n                    \u00a0knockout (KO) mice and examined their dry eye phenotype and meibum lipid composition. These mice showed a severe dry eye phenotype, characterized by plugged meibomian gland orifices, corneal damage, and tear film instability. The plugging was attributed to an increase in the melting point of the meibum lipids. Liquid chromatography coupled with tandem mass spectrometry revealed that FAl\u2010containing meibum lipids (wax monoesters and types 1\u03c9, 2\u03b1, and 2\u03c9 wax diesters) with a hydroxyl group at position 1 were almost completely absent in\n                    <jats:italic>Far2<\/jats:italic>\n                    \u00a0KO mice. The levels of di\u2010unsaturated (\n                    <jats:italic>O<\/jats:italic>\n                    \u2010acyl)\u2010\u03c9\u2010hydroxy fatty acids were higher in\n                    <jats:italic>Far2<\/jats:italic>\n                    \u00a0KO mice than in wild type mice, but those of tri\u2010unsaturated ones were comparable, suggesting the presence of two synthesis pathways for type 1\u03c9 wax diesters. These results indicate the importance of FAl\u2010containing meibum lipids in the formation of a functional tear film lipid layer. In addition, our study provides clues to the molecular mechanism of the biosynthesis of meibum lipids.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101733r","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T20:00:15Z","timestamp":1646251215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Formation of fatty alcohols\u2014components of meibum lipids\u2014by the fatty acyl\u2010CoA reductase FAR2 is essential for dry eye prevention"],"prefix":"10.1096","volume":"36","author":[{"given":"Kento","family":"Otsuka","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Sawai\u2010Ogawa","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences Hokkaido 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