Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates wound healing and mitochondrial metabolism in the cornea

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dc.creatorLiang, Wentao
dc.creatorHuang, Li
dc.creatorWhelchel, Amy E.
dc.creatorYuan, Tian
dc.creatorMa, Xiang
dc.creatorCheng, Rui
dc.creatorTakahashi, Yusuke
dc.creatorKaramichos, Dimitrios
dc.creatorMa, Jian-Xing
dc.creator.orcid0000-0002-8761-3824 (Karamichos, Dimitrios)
dc.date.accessioned2023-04-12T20:00:11Z
dc.date.available2023-04-12T20:00:11Z
dc.date.issued2023-03-22
dc.description.abstractDiabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha) expression was downregulated in diabetic human corneas. Even without diabetes, global PPARalpha knockout mice and corneal epithelium-specific PPARalpha conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARalpha agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific PPARalpha transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARalpha agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of PPARalpha, suggesting a PPARalpha-dependent mechanism. These findings suggest that downregulation of PPARalpha plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.
dc.identifier.citationLiang, W., Huang, L., Whelchel, A., Yuan, T., Ma, X., Cheng, R., Takahashi, Y., Karamichos, D., & Ma, J. X. (2023). Peroxisome proliferator-activated receptor-α (PPARα) regulates wound healing and mitochondrial metabolism in the cornea. Proceedings of the National Academy of Sciences of the United States of America, 120(13), e2217576120. https://doi.org/10.1073/pnas.2217576120
dc.identifier.issn1091-6490
dc.identifier.issue13
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32338
dc.identifier.volume120
dc.publisherNational Academy of Science
dc.relation.urihttps://doi.org/10.1073/pnas.2217576120
dc.rights.holder© 2023 the Author(s).
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceProceedings of the National Academy of Sciences of the United States of America
dc.subjectPPARalpha
dc.subjectcornea
dc.subjectepithelium
dc.subjectmitochondria
dc.subjectwound healing
dc.subject.meshMice
dc.subject.meshHumans
dc.subject.meshAnimals
dc.subject.meshPPAR alpha / genetics
dc.subject.meshPPAR alpha / metabolism
dc.subject.meshDiabetes Mellitus, Experimental / genetics
dc.subject.meshDiabetes Mellitus, Experimental / metabolism
dc.subject.meshCornea / metabolism
dc.subject.meshWound Healing / physiology
dc.subject.meshMice, Knockout
dc.subject.meshMitochondria / metabolism
dc.titlePeroxisome proliferator-activated receptor-alpha (PPARalpha) regulates wound healing and mitochondrial metabolism in the cornea
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dc.type.materialArticle

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