Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression

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.

CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

“…These novel activities of atRA were collectedly referred to as “non-canonical” and were later found to be mediated by the Cellular Retinoic Acid Binding Protein 1 (CRABP1) [ 22 ]. These CRABP1-mediated non-canonical activities of atRA were ultimately validated in careful studies of Crabp1 knockout (CKO) mice and cultures, which also revealed the physiological/disease relevance of CRABP1 [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

“…In examining the systemic inflammatory status/potential of CKO mice, it was found that HFD-fed CKO mice all had increased systemic inflammation, indicated by invading immune cells in adipose tissue [ 28 ], increased inflammatory driver Receptor Interacting Protein 140 (RIP140) (gene name Nrip1) [ 68 ] in the blood [ 31 ], elevation in inflammatory cytokines, and significantly enhanced macrophage M1 polarization (unpublished). Previous studies also indicated that CKO mice had overall increased inflammation in the heart, indicated by increased cardiac fibrosis [ 26 ], and an altered anxiety and stress response in their HPA axis [ 32 ]. To this end, CRABP1 was found to be involved in exosome secretion from CRABP1-expressing neurons.…”

“…The multiple functions of CRABP1 would predict numerous disease conditions where CRABP1 can be involved. Indeed, CKO mice exhibited multiple phenotypes mimicking human diseases [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. In tissue cultures, it is possible to examine the effects of its best-known ligand, atRA, in eliciting non-canonical activities through CRABP1, and to demonstrate holo- and apo-CRABP1’s functions in specific cell types.…”

Alteration of peripheral cortisol and autism spectrum disorder: A meta-analysis

“…A compelling body of evidence implicates that the activation of the HPA axis and pulsatile release of glucocorticoids play critical roles in response to physical or psychological stressors in physiological status (6). A growing literature has implicated that the HPA axis contributes to the development of psychiatry disorders, such as depression, anxiety, and PTSD (7)(8)(9). Animal studies suggested that the HPA axis dysfunction caused by environmental components could induce autism-like behaviors, and regulation of the HPA axis could alleviate autism-like behaviors (10).…”

Modulation of adipose inflammation by cellular retinoic acid-binding protein 1

“…Besides binding RA, CRABP1 is known to modulate at least two cytosolic signaling, MAPK and CaMKII, pathways in a cell context-dependent manner [ 22 ]. While its functional roles in several cell types have been uncovered recently, including neuron differentiation [ 23 ], neuronal exosome secretion [ 24 ], endocrine homeostasis [ 25 ], and cardiomyocyte function [ 26 ], how CRABP1 functions specifically in adipocytes remain elusive. Importantly, we have found that Crabp1 gene expression is tightly regulated during adipocyte differentiation, through hormonal induction followed by epigenetic silencing [ 27 ].…”