Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression
Retinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypot...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/22/12240 |
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| author | Yu-Lung Lin Chin-Wen Wei Thomas A. Lerdall Jennifer Nhieu Li-Na Wei |
| author_facet | Yu-Lung Lin Chin-Wen Wei Thomas A. Lerdall Jennifer Nhieu Li-Na Wei |
| author_sort | Yu-Lung Lin |
| collection | DOAJ |
| description | Retinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypothalamus and pituitary glands. Crabp1 knockout (CKO) mice exhibit reduced anxiety-like behaviors accompanied by a lowered stress induced-corticosterone level. Furthermore, CRH/DEX tests show an increased sensitivity (hypersensitivity) of their feedback inhibition in the hypothalamic–pituitary–adrenal (HPA) axis. Gene expression studies show reduced FKBP5 expression in CKO mice; this would decrease the suppression of glucocorticoid receptor (GR) signaling thereby enhancing their feedback inhibition, consistent with their dampened corticosterone level and anxiety-like behaviors upon stress induction. In AtT20, a pituitary gland adenoma cell line elevating or reducing Crabp1 level correspondingly increases or decreases FKBP5 expression, and its endogenous Crabp1 level is elevated by GR agonist dexamethasone or RA treatment. This study shows, for the first time, that Crabp1 regulates feedback inhibition of the the HPA axis by modulating FKBP5 expression. Furthermore, RA and stress can increase Crabp1 level, which would up-regulate FKBP5 thereby de-sensitizing feedback inhibition of HPA axis (by decreasing GR signaling) and increasing the risk of stress-related disorders. |
| first_indexed | 2024-03-10T05:26:25Z |
| format | Article |
| id | doaj.art-388a3bb4bf3146c09567ed23593afeac |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:26:25Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-388a3bb4bf3146c09567ed23593afeac2023-11-22T23:39:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221224010.3390/ijms222212240Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 ExpressionYu-Lung Lin0Chin-Wen Wei1Thomas A. Lerdall2Jennifer Nhieu3Li-Na Wei4Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USARetinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypothalamus and pituitary glands. Crabp1 knockout (CKO) mice exhibit reduced anxiety-like behaviors accompanied by a lowered stress induced-corticosterone level. Furthermore, CRH/DEX tests show an increased sensitivity (hypersensitivity) of their feedback inhibition in the hypothalamic–pituitary–adrenal (HPA) axis. Gene expression studies show reduced FKBP5 expression in CKO mice; this would decrease the suppression of glucocorticoid receptor (GR) signaling thereby enhancing their feedback inhibition, consistent with their dampened corticosterone level and anxiety-like behaviors upon stress induction. In AtT20, a pituitary gland adenoma cell line elevating or reducing Crabp1 level correspondingly increases or decreases FKBP5 expression, and its endogenous Crabp1 level is elevated by GR agonist dexamethasone or RA treatment. This study shows, for the first time, that Crabp1 regulates feedback inhibition of the the HPA axis by modulating FKBP5 expression. Furthermore, RA and stress can increase Crabp1 level, which would up-regulate FKBP5 thereby de-sensitizing feedback inhibition of HPA axis (by decreasing GR signaling) and increasing the risk of stress-related disorders.https://www.mdpi.com/1422-0067/22/22/12240Crabp1anxietyHPA axisretinoic acidstressFKBP5 |
| spellingShingle | Yu-Lung Lin Chin-Wen Wei Thomas A. Lerdall Jennifer Nhieu Li-Na Wei Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression International Journal of Molecular Sciences Crabp1 anxiety HPA axis retinoic acid stress FKBP5 |
| title | Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression |
| title_full | Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression |
| title_fullStr | Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression |
| title_full_unstemmed | Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression |
| title_short | Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression |
| title_sort | crabp1 modulates hpa axis homeostasis and anxiety like behaviors by altering fkbp5 expression |
| topic | Crabp1 anxiety HPA axis retinoic acid stress FKBP5 |
| url | https://www.mdpi.com/1422-0067/22/22/12240 |
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