Sleep Deprivation Induces Dry Eye Through Inhibition Of Ppar Alpha Expression In Corneal Epithelium

PURPOSE. To determine if sleep deprivation induces dry eye through altering peroxisome proliferator-activated receptor alpha (PPAR alpha) expression in mice.METHODS. The "stick over water" sleep deprivation-induced dry eye (SDE) model evaluated PPAR alpha involvement in inducing this condition. Scanning electron microscopy (SEM) examined microvilli morphology in superficial corneal epithelial cells (SCECs) in SDE and PPAR alpha(-/-) mice. Quantitative RT-PCR (qRT-PCR) and Western blot (WB) or immunostaining evaluated PPAR alpha, carnitine palmitoyl transferase 1 alpha (CPT1 alpha), and transient receptor potential vanilloid 6 (TRPV6) expression levels and Ezrin phosphorylation status. Hematoxylin-eosin and Oil Red O staining characterized meibomian gland morphology and corneal lipid accumulation, respectively. Phenol red cotton threads measured tear production. In cultured corneal epithelial sheets, qRT-PCR, WB, and SEM determined the individual effects of fenofibrate and MK886 (PPAR alpha agonist and antagonist, respectively) on PPAR alpha, TRPV6 expression, and SCEC microvilli morphology.RESULTS. Corneal epithelial lipid accumulation, microvilli morphologic changes, and decreased tear production were associated with marked declines in PPAR alpha, CPT1 alpha, and TRPV6 expression levels as well as Ezrin phosphorylation status, whereas meibomian glands were unaltered in SDE mice. These effects of SDE mice mimicked those in their nonstressed PPAR alpha(-/-) counterpart. Topical application of fenofibrate reversed these effects in SDE corneas. In cultured corneal epithelial sheets, fenofibrate increased PPAR alpha and TRPV6 gene and protein expression levels and restored microvilli morphology, whereas MK886 attenuated these changes.CONCLUSIONS. Sleep deprivation induces dry eye through abnormal SCEC microvilli morphology, which is caused by sequential downregulation of PPAR alpha, TRPV6 expression, and Ezrin phosphorylation status in mice.