Abstract
Purpose :
The gene/enzyme pair Soat1/SOAT1 was previously shown to be critical for making cholesteryl esters (CEs) in the mouse Meibomian glands (MGs) as the loss of its function in MGs led to arrest of CE production, accumulation of free cholesterol in meibum, and major changes in its rheological properties. The purpose of this study was to investigate the role of Soat1/SOAT1 in meibogenesis and ocular surface (patho)physiology using Soat1 knockout (Soat1-/-) mice as animal models of human MG dysfunction (MGD).
Methods :
Age matched male and female Soat1-/- mice and their wild type (WT) littermates were used in this study. Ocular surface (OS) damage was assessed via fluorescein staining using a slit lamp. Freshly harvested tarsal plates (TPs) were used for RNA extraction or processed for histology and histochemistry. TP transcriptomes were analyzed using Clariom D microarrays and RNA expression data was processed in the Expression Console software package and transcriptome analysis console. Mouse TPs and corneas were evaluated by H&E, Oil Red O, and/or LipidTox staining.
Results :
Slit lamp examination of Soat1-/- mice demonstrated an increase in fluorescein staining (P<0.001) of the OS in comparison with WT mice. After 5 months of age, about half of Soat1-/- mice developed corneal ulcers. Lipid staining of knockout MGs revealed minimal lipid accumulation in the acini with most of the lipid staining within the central ducts compared to the robust staining throughout the acini and central ducts of WT mice. Comparative transcriptomic analysis of Soat1-/- vs. WT mice demonstrated upregulation of about 980 coding genes and downregulation of >1,400 genes (p<0.05; 2<Fold Change<-2). The major significantly upregulated pathways included cholesterol and bile acid metabolism, formation of the cornified envelope, keratinization, inflammation, and apoptosis. Among suppressed pathways were lipid metabolism, muscle contraction, Ca(II) signaling, creatine-phosphate metabolism, signal transduction, immune response, and others.
Conclusions :
Inactivation of Soat1/SOAT1 leads to severe changes in the OS physiology, and MG biochemistry and morphology that resemble certain types of human MGD. The transcriptomic data were consistent with the Soat1-/- mouse phenotype and biochemical changes in their meibum. The Soat1-/- mice can be used as a useful model of human MGD.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.