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About the Authors:
Sandeep Dave
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Ravikanth Nanduri
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Hedwin Kitdorlang Dkhar
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Ella Bhagyaraj
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Alka Rao
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Pawan Gupta
* Email: [email protected]
Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India
Introduction
All-trans-retinoic acid (atRA) is an active hormonal form of vitamin A. RA serves as a ligand and regulates gene expression through two classes of nuclear retinoid receptors, RA receptors (RARα, RARβ, RARγ) and retinoid X receptors (RXRα, RXRβ, RXRγ) [1],[2]. It is generally accepted that nuclear retinoid receptors mediate the biological activity of RA. However, a correlation is not always seen between RA's affinity to RAR and its biological potency [3]–[9]. Non-genomic mechanisms such as retinoylation (acylation by RA) of proteins have been identified but not adequately addressed [6],[10]–[16]. Positive correlations have been reported between the retinoylation reaction and testosterone biosynthesis [17], embryonic carcinoma cell differentiation [18],[19], and fibroblast cell growth [20],[21].
RA incorporation with proteins have been validated in both in vitro [10],[22],[23] and in vivo experimental setups [10],[23]–[25]. Significant retinoylated protein mass has been observed in tissues or cells of testis, brain, kidney, liver and fibroblasts, yet only a short list of retinoylated proteins have been identified. The list includes regulatory subunits of cAMP-dependent protein kinase I and II, vimentin, the cytokeratins, ribonucleotide reductase, 2-oxoglutarate/malate carrier protein, and nuclear proteins such as histone deacetylase 3 (HDAC3) [26]–[31]. The covalent linkage between RA and proteins is probably a thioester and involves formation of a coenzyme A (CoA) intermediate [13],[23],[32],[33]. The retinoylation reaction displays rapid kinetics (12–24 h). The optimal concentration of RA for the retinoylation reaction is 100 nM–1 µM [22],[34],[35]. atRA is an inhibitor of adipocyte differentiation [7],[36] and an effective anti-obesity nutritional supplement [37], however the mechanism for these actions has remained elusive. This inhibitory effect depends on the concentration and stage of differentiation of the adipocytes. atRA has been clearly shown to inhibit adipocyte differentiation at relatively high doses (100 nM–10 µM) and in a narrow window (0–48 h) at the early stages of adipogenesis [36].
Retinoylated proteins have been identified in 3T3 fibroblasts, an upstream lineage of adipocytes [8], a...