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Abstract
Meibum lipids form a lipid layer on the outermost side of the tear film and function to prevent water evaporation and reduce surface tension. (O-Acyl)-ω-hydroxy fatty acids (OAHFAs), a subclass of these lipids, are thought to be involved in connecting the lipid and aqueous layers in tears, although their actual function and synthesis pathway have to date remained unclear. Here, we reveal that the fatty acid ω-hydroxylase Cyp4f39 is involved in OAHFA production. Cyp4f39-deficient mice exhibited damaged corneal epithelium and shortening of tear film break-up time, both indicative of dry eye disease. In addition, tears accumulated on the lower eyelid side, indicating increased tear surface tension. In Cyp4f39-deficient mice, the production of wax diesters (type 1ω and 2ω) and cholesteryl OAHFAs was also impaired. These OAHFA derivatives show intermediate polarity among meibum lipids, suggesting that OAHFAs and their derivatives contribute to lipid polarity gradient formation for tear film stabilization.
Highlights
The tear film maintains visual function by eliminating foreign materials, supplying oxygen and nutrients to the ocular surface, and reducing friction between the eyelid and the ocular globe (Ohashi et al, 2006)
To examine the involvement of Cyp4f39 in OAHFA production in the meibomian glands, the neonatal lethality caused by whole-body Cyp4f39 disruption must be circumvented
To confirm the epidermis-specific expression of 3ÂFLAG-Cyp4f39 protein, total cell lysates were prepared from several tissues of Tg-Cyp4f39–/– mice and subjected to immunoblotting with anti-FLAG antibody. 3ÂFLAG-Cyp4f39 was highly expressed in the epidermis, and weak expression was observed in the cornea and meibomian glands (Figure 1D)
Summary
The tear film maintains visual function by eliminating foreign materials, supplying oxygen and nutrients to the ocular surface (cornea and conjunctiva), and reducing friction between the eyelid and the ocular globe (Ohashi et al, 2006). It is postulated that this sublayer functions in stabilizing tear film by producing an interface between the nonpolar lipid layer, which constitutes most of the TFLL, and the aqueous layer beneath it (Butovich et al, 2009). Whole-body Cyf4f39 gene knockout is neonatal lethal (Miyamoto et al, 2020), so we created Cyp4f39–/– Tg (IVL-Cyp4f39) mice (hereafter, Tg-Cyp4f39–/–), in which the epidermal barrier defect was rescued by the transgenic expression of Cyp4f39 in the epidermis. Using these mice, we examined the involvement of Cyp4f39 in the production of OAHFAs and OAHFA derivatives, and their roles in tear film stabilization
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