Steroid specificity of the putative DHB receptor: evidence that the receptor is not 11βHSD

Sheppard, Karen E.; Khoo, Karen; Krozowski, Zygmunt; Li, Kevin X. Z.

doi:10.1152/ajpendo.1998.275.1.e124

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…Cells were detached along the crypt axis in apical to basal direction, thus surface epithelial cells were liberated earlier than cells at the crypt base [22]. Due to its subcellular localization, 11β-HSD2 activity was present in both nuclear and microsomal pellets of human and rat colon, but not in cytosol when no detergent was added [26], [27]. These technical details, well standardized for the present investigation may explain at least in part the discrepancies observed between our results and the results reported for intestinal 11β-HSD2.…”

Section: Discussionmentioning

confidence: 99%

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

et al. 2012

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Besides the kidneys, the gastrointestinal tract is the principal organ responsible for sodium homeostasis. For sodium transport across the cell membranes the epithelial sodium channel (ENaC) is of pivotal relevance. The ENaC is mainly regulated by mineralocorticoid receptor mediated actions. The MR activation by endogenous 11β-hydroxy-glucocorticoids is modulated by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Here we present evidence for intestinal segment specific 11β-HSD2 expression and hypothesize that a high salt intake and/or uninephrectomy (UNX) affects colonic 11β-HSD2, MR and ENaC expression. The 11β-HSD2 activity was measured by means of 3H-corticosterone conversion into 3H-11-dehydrocorticosterone in Sprague Dawley rats on a normal and high salt diet. The activity increased steadily from the ileum to the distal colon by a factor of about 3, an observation in line with the relevance of the distal colon for sodium handling. High salt intake diminished mRNA and protein of 11β-HSD2 by about 50% (p<0.001) and reduced the expression of the MR (p<0.01). The functionally relevant ENaC-β and ENaC-γ expression, a measure of mineralocorticoid action, diminished by more than 50% by high salt intake (p<0.001). The observed changes were present in rats with and without UNX. Thus, colonic epithelial cells appear to contribute to the protective armamentarium of the mammalian body against salt overload, a mechanism not modulated by UNX.

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Section: Discussionmentioning

confidence: 99%

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

et al. 2012

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“…3A). Recently, 5a-DHB has also been suggested as a ligand for a putative, alternative DHB receptor (Sheppard et al 1998).…”

Section: Actions Of Substrate Vs Productmentioning

confidence: 99%

5α-Reduced glucocorticoids: a story of natural selection

Nixon¹,

Upreti²,

Andrew³

2011

Journal of Endocrinology

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5a-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5a-reductase reduces the D 4-5 double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5a-dihydro steroids, e.g. 5a-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5a-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5a-Dihydro-and 5a-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5a-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5a-reduced metabolite may critically affect the profile of GR signalling. 5a-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5a-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5a-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.

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“…In cells expressing high levels of 11␤HSD2, B binding to both MR and GR is compromised (29,32). Therefore, it is conceivable that there are cellular mechanisms that would allow endogenous, albeit transformed, glucocorticoids to bind receptor and thus mediate glucocorticoid effects.…”

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confidence: 99%

Novel nuclear corticosteroid binding in rat small intestinal epithelia

Sheppard

Hourigan

et al. 2000

American Journal of Physiology-Gastrointestinal and Liver Physi

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When small intestinal epithelial cells are incubated with [(3)H]corticosterone, nuclear binding is displaced neither by aldosterone nor RU-28362, suggesting that [(3)H]corticosterone is binding to a site distinct from mineralocorticoid receptor and glucocorticoid receptor. Saturation and Scatchard analysis of nuclear [(3)H]corticosterone binding demonstrate a single saturable binding site with a relatively low affinity (49 nM) and high capacity (5 fmol/microg DNA). Competitive binding assays indicate that this site has a unique steroid binding specificity, which distinguishes it from other steroid receptors. Steroid specificity of nuclear binding mirrors inhibition of the low 11beta-dehydrogenase activity, suggesting that binding may be to an 11beta-hydroxysteroid dehydrogenase (11betaHSD) isoform, although 11betaHSD1 is not present in small intestinal epithelia and 11betaHSD2 does not colocalize intracellularly with the binding site. In summary, a nuclear [(3)H]corticosterone binding site is present in small intestinal epithelia that is distinct from other steroid receptors and shares steroid specificity characteristics with 11betaHSD2 but is distinguishable from the latter by its distinct intracellular localization.

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Steroid specificity of the putative DHB receptor: evidence that the receptor is not 11βHSD

Cited by 4 publications

References 39 publications

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

5α-Reduced glucocorticoids: a story of natural selection

Novel nuclear corticosteroid binding in rat small intestinal epithelia

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