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PURPOSE. To determine if sleep deprivation induces dry eye through altering peroxisome proliferator-activated receptor alpha (PPARa) expression in mice. METHODS. The ''stick over water'' sleep deprivation-induced dry eye (SDE) model evaluated PPARa involvement in inducing this condition. Scanning electron microscopy (SEM) examined microvilli morphology in superficial corneal epithelial cells (SCECs) in SDE and PPARa À/À mice. Quantitative RT-PCR (qRT-PCR) and Western blot (WB) or immunostaining evaluated PPARa, carnitine palmitoyl transferase 1a (CPT1a), 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 (PPARa agonist and antagonist, respectively) on PPARa, TRPV6 expression, and SCEC microvilli morphology. RESULTS. Corneal epithelial lipid accumulation, microvilli morphologic changes, and decreased tear production were associated with marked declines in PPARa, CPT1a, 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 PPARa À/À counterpart. Topical application of fenofibrate reversed these effects in SDE corneas. In cultured corneal epithelial sheets, fenofibrate increased PPARa 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 PPARa, TRPV6 expression, and Ezrin phosphorylation status in mice.

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