The Properties and Role of O-Acyl-ω-hydroxy Fatty Acids and Type I-St and Type II Diesters in the Tear Film Lipid Layer Revealed by a Combined Chemistry and Biophysics Approach.

Tuomo Viitaja,Filip S Ekholm,Jukka Moilanen,Riku O Paananen,Jan-Erik Raitanen

doi:10.1021/acs.joc.0c02882

Tuomo Viitaja, Filip S Ekholm + Show 3 more

Open Access

https://doi.org/10.1021/acs.joc.0c02882

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Abstract

The tear film lipid layer (TFLL) that covers the ocular surface contains several unique lipid classes, including O-acyl-ω-hydroxy fatty acids, type I-St diesters, and type II diesters. While the TFLL represents a unique biological barrier that plays a central role in stabilizing the entire tear film, little is known about the properties and roles of individual lipid species. This is because their isolation from tear samples in sufficient quantities is a tedious task. To provide access to these species in their pure form, and to shed light on their properties, we here report a general strategy for the synthesis and structural characterization of these lipid classes. In addition, we study the organization and behavior of the lipids at the air–tear interface. Through these studies, new insights on the relationship between structural features, such as number of double bonds and the chain length, and film properties, such as spreading and evaporation resistance, were uncovered.

Highlights

The tear film lipid layer (TFLL) resides on top of the tear film, where it covers the ocular surface and protects and lubricates the surface of the eye (Figure 1)
We performed a detailed retrosynthetic analysis, which revealed that the O-acyl-ω-hydroxy fatty acids (OAHFAs) and its type I-St and type II diesters can all be constructed from one common core intermediate
We focused solely on the preparation of a short 20:1OAHFA and its type I-St cholesteryl and type II oleoyl diesters

Summary

INTRODUCTION

The tear film lipid layer (TFLL) resides on top of the tear film, where it covers the ocular surface and protects and lubricates the surface of the eye (Figure 1). The TFLL contains several unique classes of lipids that are characterized by ultralong unsaturated hydrocarbon chains, including O-acyl-ω-hydroxy fatty acids (OAHFAs) and type I-St (cholesteryl) and type II (wax) diesters (Figure 1).[10] Each of these special lipid classes constitutes a relatively small fraction (3−4 mol % each) of the total lipids in Meibomian gland secretions, recent results have suggested that they may be central to TFLL function.[11−14] OAHFAs have been proposed to be potential indicators of DED progression, and a consistent decrease in the number of OAHFA species has been correlated to DED severity in patient-derived meibum samples.[15] While a positive correlation between the Schirmer I test and the tear film breakup time for the total OAHFA levels has been noted,[14] uncertainties still remain since statistically significant decreases in total tear OAHFA levels has not been confirmed in DED patients.[15] reduced levels of type I-St and type II diesters have been reported in patient-derived tear samples compared to those in healthy controls.[16] animal studies have shown that the knockout of the Cyp4f39-gene involved in the synthesis of OAHFAs and their related diesters in the Meibomian glands leads to the development of a severe dry eye phenotype in mice.[17] there are indications that OAHFAs and their diester derivatives may be central to proper TFLL function. Type I-St diesters were found to exhibit a liquidcrystalline structure at the aqueous interface, suggesting their involvement in the multilamellar organization of the TFLL

RESULTS AND DISCUSSION

CONCLUSION

EXPERIMENTAL SECTION

■ ACKNOWLEDGMENTS

■ REFERENCES