Biosynthesis of fatty aldehydes and alcohols in the eye and their role in meibogenesis.

Fatty alcohols (FAlc) and aldehydes (FAld) are essential intermediates/precursors in the biosynthesis of lipids. However, elevated FAld levels were shown to be geno- and cytotoxic, and, thus, requiring conversion into less toxic FAlc and fatty acids (FA). An increase in FAlc and FAld in tissues of patients with Sjögren-Larsson syndrome was reported before and repeatedly linked to inactivation of ALDH3A2, which oxidizes FAld in FA. Recently, we hypothesized that another group of enzymes, namely SDR16C5/SDR16C6 (EC 1.1.1.105), could control the balance between FA, FAlc, and FAld via a separate mechanism. In this study, we assessed the in vivo biosynthesis of FAlc and FAld in mammals using Meibomian glands (MG) of wild type (WT) and Sdr16c5/Sdr16c6-null (Hom) mice as models. Lipids were extracted from MG of experimental animals and analyzed using LC/MS. Because of high reactivity and instability of FAld, the compounds were initially converted to stable, sodium borohydride-reduced 3-aminopyridine conjugates, while FAlc were analyzed as N-alkyl pyridinium ions. A wide range of saturated and unsaturated FAld, FAlc, and FA ranging from C₃ to C₂₈ and longer were found in MG of mice of both genotypes. Our experiments revealed a multifold upregulation of almost all detected straight chain, but not branched, FAlc in MG lipidomes of Hom mice, which implied a previously unknown ability of SDR16C5/SDR16C6 to oxidize a wide range of FAlc in FAld in vivo. We have concluded that SDR16C5/SDR16C6 play a central, and selective, role in FA/FAlc/FAld metabolism in vivo, and proposed a generalized mechanism of these reactions.