Abstract
Abstract: :
Purpose: We have recently discovered that the meibomian gland is an androgen target organ, that androgens modulate lipid production within this tissue, and that androgen deficiency is associated with glandular dysfunction and evaporative dry eye. This study's purpose was to test our hypothesis that androgen control of the meibomian gland, as with other sebaceous glands, involves the regulation of gene expression. Methods: Meibomian glands were obtained from orchiectomized mice (n = 18-22/group), that were treated with placebo or testosterone for 14 days. Tissues were processed for the analysis of differentially expressed mRNAs by using GEM 1 (≷ 8,000 genes) and GEM 2 (≷ 9,500 genes) gene chips, Rosetta Resolver software, and/or real-time PCR. Results: Testosterone influenced the expression of over 110 genes in the mouse meibomian gland. Of particular interest, androgen exposure upregulated genes involved in lipid, sex steroid and other cellular metabolic pathways, such as sterol regulatory element binding proteins 1 and 2 (transcription factors that coordinately regulate lipogenic enzymes), fatty acid (FA) synthase, ATP-citrate lyase and acetyl-CoA-carboxylase (all key enzymes in lipid metabolism), monoglyceride lipase (an enzyme involved in lipid hydrolysis), FA transport protein 4 (a protein that promotes cellular uptake and metabolism of long chain FA), Abca1 and Abcd3 (ABC transporter family members and involved in lipid transport across cellular membranes), scavenger receptor class B type I (mediates uptake of specific lipids into steroidogenic tissues), 17b-hydroxysteroid dehydrogenase 7 (an essential enzyme involved in the intracrine synthesis of sex steroids), nuclear receptor coactivator 4 (an androgen receptor coactivator) and insulin-like growth factor 1 (involved in sebaceous cell DNA synthesis and differentiation). In contrast, androgen treatment was associated with a downregulation of the cyclin D1 gene (a factor that may inhibit androgen receptor transactivation). Conclusion: These findings indicate that testosterone regulates the expression of numerous critical genes in the mouse meibomian gland. (Supported by research grants from NIH [EY05612 & 12523], Allergan and the German Research Society DFG)
Keywords: 376 cornea: tears/tear film/dry eye • 417 gene/expression • 458 lipids