Glucocorticoid Receptor
The glucocorticoid receptor (GR, NR3C1) is expressed in brain in both
rodent and human, in neurons, glia and vascular epithelial cells (de
Kloet, Meijer, de Nicola, de Rijk & Joels, 2018; Tanaka, Fujita,
Matsuda, Toku, Sakanaka & Maeda, 1997). The GR is most widely expressed
in stress related centres yet within these regions there is differential
expression over time. Besides cortisol and corticosterone, the steroid
hormone ligands towards GR, this receptor is also activated by
3β,5α-dihydroxycholestan-6-one (3β,5α-diHC-6O, also called
6-oxocholestan-3β,5α-diol, OCDO, see inset Figure 1), a recently
discovered oxysterol derived from cholestane-3β,5α,6β-triol through
enzymatic oxidation by hydroxysteroid dehydrogenase 11B2 (HSD11B2)
(Voisin et al., 2017), an enzyme expressed in brain (Holmes et al.,
2006). Cholestane-3β,5α,6β-triol itself is derived from
5,6-epoxycholesterol (5,6-EC) by the enzyme cholesterol-5,6-epoxide
hydrolase (ChEH), an enzyme derived from two subunits DHCR7
(dehydrocholesterol reductase 7) and D8D7I
(3β-hydroxystero-delta-8,7-isomerase), however, the enzymatic origin of
5,6-EC has yet to be defined (de Medina, Paillasse, Segala, Poirot &
Silvente-Poirot, 2010). In the context of neuro-oxysterols 3β,5α-diHC-6O
(OCDO) has been found to be exported from human brain indicating its
biosynthesis in this organ (Iuliano et al., 2015).