Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction
Abstract The diabetes mellitus (DM) skin shows skin barrier dysfunction and skin lipid abnormality, similar to conditions induced by systemic or local glucocorticoid excess and aged skin. Inactive glucocorticoid (GC) is converted into active glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1...
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| Format: | Article |
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Nature Portfolio
2023-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-36294-y |
| _version_ | 1797806783146754048 |
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| author | Young Bin Lee Hyun Jee Hwang Eunjung Kim Sung Ha Lim Choon Hee Chung Eung Ho Choi |
| author_facet | Young Bin Lee Hyun Jee Hwang Eunjung Kim Sung Ha Lim Choon Hee Chung Eung Ho Choi |
| author_sort | Young Bin Lee |
| collection | DOAJ |
| description | Abstract The diabetes mellitus (DM) skin shows skin barrier dysfunction and skin lipid abnormality, similar to conditions induced by systemic or local glucocorticoid excess and aged skin. Inactive glucocorticoid (GC) is converted into active glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Hyperglycemia in DM and excessive GC are known to increase endoplasmic reticulum (ER) stress. We hypothesized that hyperglycemia affects systemic GC homeostasis and that the action of skin 11β-HSD1 and GC contributes to increased ER stress and barrier defects in DM. We compared 11β-HSD1, active GC, and ER stress between hyperglycemic and normoglycemic conditions in normal human keratinocytes and db/db mice. 11β-HSD1 and cortisol increased with time in keratinocyte culture under hyperglycemic conditions. 11β-HSD1 siRNA-transfected cells did not induce cortisol elevation in hyperglycemic condition. The production of 11β-HSD1 and cortisol was suppressed in cell culture treated with an ER stress-inhibitor. The 14-week-old db/db mice showed higher stratum corneum (SC) corticosterone, and skin 11β-HSD1 levels than 8-week-old db/db mice. Topical 11β-HSD1 inhibitor application in db/db mice decreased SC corticosterone levels and improved skin barrier function. Hyperglycemia in DM may affect systemic GC homeostasis, activate skin 11β-HSD1, and induce local GC excess, which increases ER stress and adversely affects skin barrier function. |
| first_indexed | 2024-03-13T06:12:35Z |
| format | Article |
| id | doaj.art-76ad8e81478a48d6a7be2472087dbb89 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T06:12:35Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-76ad8e81478a48d6a7be2472087dbb892023-06-11T11:10:18ZengNature PortfolioScientific Reports2045-23222023-06-0113111310.1038/s41598-023-36294-yHyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunctionYoung Bin Lee0Hyun Jee Hwang1Eunjung Kim2Sung Ha Lim3Choon Hee Chung4Eung Ho Choi5Department of Dermatology, Yonsei University Wonju College of MedicineDepartment of Dermatology, Yonsei University Wonju College of MedicineDepartment of Dermatology, Yonsei University Wonju College of MedicineDepartment of Dermatology, Yonsei University Wonju College of MedicineDepartment of Endocrinology and Metabolism, Yonsei University Wonju College of MedicineDepartment of Dermatology, Yonsei University Wonju College of MedicineAbstract The diabetes mellitus (DM) skin shows skin barrier dysfunction and skin lipid abnormality, similar to conditions induced by systemic or local glucocorticoid excess and aged skin. Inactive glucocorticoid (GC) is converted into active glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Hyperglycemia in DM and excessive GC are known to increase endoplasmic reticulum (ER) stress. We hypothesized that hyperglycemia affects systemic GC homeostasis and that the action of skin 11β-HSD1 and GC contributes to increased ER stress and barrier defects in DM. We compared 11β-HSD1, active GC, and ER stress between hyperglycemic and normoglycemic conditions in normal human keratinocytes and db/db mice. 11β-HSD1 and cortisol increased with time in keratinocyte culture under hyperglycemic conditions. 11β-HSD1 siRNA-transfected cells did not induce cortisol elevation in hyperglycemic condition. The production of 11β-HSD1 and cortisol was suppressed in cell culture treated with an ER stress-inhibitor. The 14-week-old db/db mice showed higher stratum corneum (SC) corticosterone, and skin 11β-HSD1 levels than 8-week-old db/db mice. Topical 11β-HSD1 inhibitor application in db/db mice decreased SC corticosterone levels and improved skin barrier function. Hyperglycemia in DM may affect systemic GC homeostasis, activate skin 11β-HSD1, and induce local GC excess, which increases ER stress and adversely affects skin barrier function.https://doi.org/10.1038/s41598-023-36294-y |
| spellingShingle | Young Bin Lee Hyun Jee Hwang Eunjung Kim Sung Ha Lim Choon Hee Chung Eung Ho Choi Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction Scientific Reports |
| title | Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| title_full | Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| title_fullStr | Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| title_full_unstemmed | Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| title_short | Hyperglycemia-activated 11β-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| title_sort | hyperglycemia activated 11β hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction |
| url | https://doi.org/10.1038/s41598-023-36294-y |
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