Time-dependent changes in meibum lipid composition and progression of dry eye following disruption of the fatty acid elongase Elovl1

The fatty acid (FA) elongase ELOVL1 is responsible for the synthesis of very-long-chain (VLC) FAs (VLCFAs) with carbon chain lengths of ≥C21. Meibum lipids, which constitute the lipid layer of the tear film, contain several lipid classes containing VLCFAs or their metabolites, VLC fatty alcohols. In this study, we investigated the short-, medium-, and long-term effects of Elovl1 disruption on dry eye phenotypes and meibum lipid composition using two genetically engineered mouse models: epidermis-specific Elovl1 transgene-containing Elovl1 KO (Tg-Elovl1 KO) mice and tamoxifen (Tam)-inducible Elovl1 conditional KO mice. In Tg-Elovl1 KO mice, shortening of the chain lengths of cholesteryl esters, wax monoesters, and type 1ω wax diesters, as well as a reduction in the quantity of type 2ω wax diesters, was observed. These changes were also observed in a time-dependent manner in Elovl1 conditional KO mice administered Tam: in most cases, changes began on day 5 after the start of Tam administration, progressed rapidly until day 10, and then progressed more slowly thereafter. However, dry eye phenotypes (partially closed eyes, increased eye blink frequency, elevated water evaporation, plugging in the meibomian gland orifice, and tear film instability) were observed later than lipid composition changes, mostly starting from day 10 and becoming more pronounced by day 30. These findings reveal a link between alterations in meibum lipid composition and dry eye phenotypes and provide new insights into the metabolic flux of VLCFAs.