Abstract
All-trans retinoic acid (AtRA), an active metabolite of vitamin A, is recognized for its classical action as an endocrine hormone that triggers genomic effects mediated through nuclear receptors RA receptors (RARs). New evidence shows that atRA-mediated cellular responses are biphasic with rapid and delayed responses. Most of these rapid atRA responses are the outcome of its binding to cellular retinoic acid binding protein 1 (CRABP1) that is predominantly localized in cytoplasm and binds to atRA with a high affinity. This review summarizes the most recent studies of such non-genomic outcomes of atRA and the role of CRABP1 in mediating such rapid effects in different cell types. In embryonic stem cells (ESCs), atRA-CRABP1 dampens growth factor sensitivity and stemness. In a hippocampal neural stem cell (NSC) population, atRA-CRABP1 negatively modulates NSC proliferation and affects learning and memory. In cardiomyocytes, atRA-CRABP1 prevents over-activation of calcium-calmodulin-dependent protein kinase II (CaMKII), protecting heart function. These are supported by the fact that CRABP1 gene knockout (KO) mice exhibit multiple phenotypes including hippocampal NSC expansion and spontaneous cardiac hypertrophy. This indicates that more potential processes/signaling pathways involving atRA-CRABP1 may exist, which remain to be identified.
Highlights
Vitamins are essential micronutrients required for a myriad of biological processes
Questions remain to be answered when it comes to the integration of atRA with other growth factors or neuropeptides in the context of whole animals
Will hypovitaminosis A cause an abnormal neural stem cell (NSC) pool in the brain or more severe cardiac outcome? Given that cellular retinoic acid binding protein 1 (CRABP1) can intercept growth factor signaling, can CRABP1 serve as a target in cancer therapy? Classical transgenic studies of over-expressing CRABP1 demonstrate that abnormally high levels of CRABP1 can lead to abnormalities in the lung and the liver in mice [68]
Summary
Vitamins are essential micronutrients required for a myriad of biological processes. Vitamin A was first known to play an essential role in vision [1,2]. Vitamin A must be provided by one’s diet and is metabolized into different metabolites collectively called the retinoids, including retinoic acid (RA), retinol (ROL), retinal, etc., characterized based on the functional modification concatenated to the extreme end of the core scaffold [13,16]. Amongst these retinoids, various isomeric forms of RA: atRA, 9-cis-retinoic acid, and 13-cis-retinoic acid are best studied for their activities in regulating gene expression via binding to nuclear RA receptors (RARs) or retinoid X receptors (RXRs) [17,18,19,20]. This review focuses on these new findings and the emerging concept that atRA can exert specific, non-canonical (RAR/RXR-independent) physiological activities through CRABP1
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