Sleep Deprivation Induces Dry Eye Through Inhibition of PPARα Expression in Corneal Epithelium

Tang, Liying; Wang, Xue; Wu, Jieli; Li, San Ming; Zhang, Zhaoqiang; Wu, San‐Gang; Su, Ting; Zhong, Lin; Liao, Xu‐Lin; Bai, Tao; Qiu, Yan; Reinach, Peter S.; Li, Wei; Chen, Yongxiong; Liu, Zuguo

doi:10.1167/iovs.18-24504

Cited by 38 publications

(35 citation statements)

References 61 publications

(83 reference statements)

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“…PEA is an endogenous agonist of PPAR-a. In a previous study, we found that SD-induced declines in corneal PPAR-a expression result in increased corneal lipid accumulation (Tang et al, 2018). We also found that PPAR-a −/− mice have very similar corneal lipid accumulation compared to SDE mice.…”

Section: Ppar-a Mediates the Effect Of Pea On Sd-induced Lacrimal Damsupporting

confidence: 61%

“…PEA could not increase the tear production (B), reduce the LG (C) and acinar cell size (D), and ameliorate lipid deposition (E) in PPAR-a −/− mice. *, P < 0.05, **, P < 0.01 vs. control group, one-way ANOVA followed by Dunette's post hoc, n = 5. microvillus morphology, and severe LG lipid accumulation (Li et al, 2018;Tang et al, 2018). In clinical practice, use of artificial tears and anti-inflammatory eye drops is not a significant and effective treatment approach for these populations.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal superficial corneal epithelial cell microvilli morphology is another main cause of SD-induced dry eye (SDE)-like symptoms. This morphological change is associated with peroxisome proliferator-activated receptor-a (PPAR-a)mediated lipid metabolism abnormalities (Tang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation–Induced Dry Eye Syndrome

Chen

Zheng

et al. 2020

Front. Pharmacol.

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Sleep loss is a key factor associated with dry eye. Use of a "stick over water" mouse model revealed that sleep deprivation induces accumulation of lipids, hypertrophy, and dysfunction of the lacrimal gland. These changes result in decreased tear production and dry eye clinical signs. The specific pathophysiological mechanisms that contribute to dry eye remain unclear. In this study, we found that sleep deprivation decreased endogenous lipid palmitoylethanolamide (PEA) expression in the lacrimal gland. The reduced expression was mainly attributed to the decreased expression of N-acylated phosphatidylethanolamine-phospholipase D, the synthetic enzyme of PEA. Exogenous PEA treatment restored local lipid metabolism homeostasis in the lacrimal gland. This change was accompanied by reduced lipid deposition, maintenance of the endoplasmic reticulum and mitochondrial morphology, and improved acinar cell secretory function. PEA treatment also prevented damage to corneal barrier function and improved the dry eye clinical signs caused by sleep deprivation. The nuclear receptor peroxisome proliferator-activated receptor-a (PPAR-a) was found to mediate the PEA-associated improvements. We describe here for the first time that PEA is involved in sleep deprivation-induced lacrimal gland pathogenesis and dry eye development. PEA and its metabolizing enzymes may serve as adjunctive therapeutic targets for treatment of dry eye.

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Section: Ppar-a Mediates the Effect Of Pea On Sd-induced Lacrimal Damsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation–Induced Dry Eye Syndrome

Chen

Zheng

et al. 2020

Front. Pharmacol.

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“…Fenofibrate ameliorated the severity of ocular surface squamous metaplasia, commonly seen in patients with long-term deficiency of tear film [ 108 ] and suppressed the formation of tear film instability via the inhibition of macrophages and downregulation of pro-inflammatory factors [ 107 ]. In the corneal epithelium of mice with dry eyes by sleep deprivation, downregulation of PPARα expression was detected [ 109 ], and fenofibrate increased PPARα expression in cultured corneal epithelium sheets and restored microvilli morphology [ 109 ]. This implies PPARα activation could have potential for use as a preventive agent in patients with high risk of dry eye.…”

Section: Functions Of Pparα In the Eyementioning

confidence: 99%

PPARα Agonist Oral Therapy in Diabetic Retinopathy

2020

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Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

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“…Our earlier data indicate downregulation of PPAR-α expression in corneal epithelium of mice with dry eye induced by sleep deprivation. 18 However, further investigation is needed to elucidate the critical role of PPAR-α in the pathogenesis of dry eye and ocular surface squamous metaplasia. We hypothesized that activation of PPAR-α by agonists, such as fibrates, could alleviate squamous metaplasia by a mechanism similar to that of PPAR-γ.…”

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confidence: 99%

PPAR-α Agonist Fenofibrate Suppressed the Formation of Ocular Surface Squamous Metaplasia Induced by Topical Benzalkonium Chloride

Liang

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To investigate the effects and mechanisms of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate on the formation of ocular surface squamous metaplasia induced by topical benzalkonium chloride (BAC) in a mouse model. Methods Ocular surface squamous metaplasia was induced in 16 days by topical BAC application in mice. During the period of induction, mice were divided into four groups: no additional treatment (BAC+UT), topical vehicle (BAC+Vehicle), topical fenofibrate (BAC+Feno), or topical fenofibrate plus intraperitoneal injection of MK886 (BAC+Feno+MK886). The parameters of tear film were evaluated on day 16, and eye specimens were collected. Histologic investigation; PAS assays; immunostaining for cytokeratin 10 (K10), Ki67, and F4/80; and PCR assays for TNF-α and IL-6 were performed. Cell Counting Kit 8 (CCK-8) assays were performed to evaluate the inhibitory effects of fenofibrate on RAW264.7 cells. Results Fenofibrate suppressed the formation of BAC-induced instable tear film. In the BAC+Feno group, the expression of K10 and Ki67 was lower than in the other three groups. The number of goblet cells was reduced in eyes of the BAC+UT and BAC+Vehicle groups but was maintained in eyes of the BAC+Feno group. The number of F4/80-positive cells and the levels of TNF-α and IL-6 mRNA were significantly reduced in the cornea of the BAC+Feno group. These effects of fenofibrate could be attenuated by MK886. The cell viability of RAW264.7 cells could be significantly inhibited by fenofibrate in a dose-dependent pattern. Conclusions Topical application of fenofibrate suppressed the formation of ocular surface squamous metaplasia, which might be mediated through the PPAR-α signaling pathway.

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Sleep Deprivation Induces Dry Eye Through Inhibition of PPARα Expression in Corneal Epithelium

Cited by 38 publications

References 61 publications

N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation–Induced Dry Eye Syndrome

N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation–Induced Dry Eye Syndrome

PPARα Agonist Oral Therapy in Diabetic Retinopathy

PPAR-α Agonist Fenofibrate Suppressed the Formation of Ocular Surface Squamous Metaplasia Induced by Topical Benzalkonium Chloride

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