Abstract
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.
Highlights
Retinoic acid (RA) is the principal active metabolite of vitamin A and plays important roles in multiple biological systems
We used a pituitary gland cell line, AtT20, which expressed cellular RA binding protein 1 (Crabp1) endogenously. In this physiologically relevant in vitro model, we found that lowering Crabp1 level resulted in down-regulated FK506-binding protein 51 (FKBP5) expression
The physiological relevance of RA induction of this gene in pituitary gland cells remains to be determined further. This is the first study uncovering the physiological relevance of Crabp1 to the stress response
Summary
Retinoic acid (RA) is the principal active metabolite of vitamin A and plays important roles in multiple biological systems. In the central nervous system, RA is best known to regulate neurogenesis and synaptic plasticity during developmental stages. Clinical and pre-clinical studies have shown that retinoids may contribute to stress-related disorders, such as depression and anxiety. Hypervitaminosis A is associated with psychiatric disorders such as depression, aggression, and psychosis [1,2,3]. The compound 13-cis RA (isotretinoin; ITT) is an FDA-approved drug for severe acne, but has serious side effects including depression, suicidal ideation and psychosis [3]. Chronic treatment with RA or ITT induces anxiety- and depression-like behaviors and impairs homeostasis of the hypothalamic–pituitary–adrenal (HPA) axis in preclinical studies [4]. All the evidence suggests that excess RA can contribute to stress-related disorders, likely through disrupting HPA axis regulation.
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