Document Detail


Rapid mechanisms of glucocorticoid signaling in the Leydig cell.
MedLine Citation:
PMID:  18281069     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type 1 isoform of 11beta-hydroxysteroid dehydrogenase (11betaHSD1). This enzyme is bidirectional (with both oxidase and reductase activities) and in the rat testis is exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids. The predominant reductase direction of 11betaHSD1 activity in liver cells is determined by an enzyme, hexose-6-phosphate dehydrogenase (H6PDH), on the luminal side of the smooth endoplasmic reticulum (SER). Generation of the pyridine nucleotide cofactor NADPH by H6PDH stimulates the reductase direction of 11betaHSD1 resulting in increased levels of active glucocorticoids in liver cells. Unlike liver cells, steroidogenic enzymes including 17beta-hydroxysteroid dehydrogenase 3 (17betaHSD3) forms the coupling with 11betaHSD1. Thus the physiological concentrations of androstenedione serve as a substrate for 17betaHSD3 utilizing NADPH to generate NADP+, which drives 11betaHSD1 in Leydig cells primarily as an oxidase; thus eliminating the adverse effects of glucocorticoids on testosterone production. At the same time 11betaHSD1 generates NADPH which promotes testosterone biosynthesis by stimulating 17betaHSD3 in a cooperative cycle. This enzymatic coupling constitutes a rapid mechanism for modulating glucocorticoid control of testosterone biosynthesis. Under stress conditions, glucocorticoids also have rapid actions to suppress cAMP formation thus to lower testosterone production.
Authors:
Guo-Xin Hu; Qing-Quan Lian; Han Lin; Syed A Latif; David J Morris; Matthew P Hardy; Ren-Shan Ge
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2007-12-28
Journal Detail:
Title:  Steroids     Volume:  73     ISSN:  0039-128X     ISO Abbreviation:  Steroids     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-06-06     Completed Date:  2008-09-03     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0404536     Medline TA:  Steroids     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1018-24     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Animals
Cell Membrane / metabolism
Dose-Response Relationship, Drug
Glucocorticoids / metabolism*
Humans
Leydig Cells / metabolism*
Liver / cytology
Male
Models, Biological
NADP / metabolism
Rats
Receptors, Glucocorticoid / metabolism
Signal Transduction
Testosterone / metabolism
Grant Support
ID/Acronym/Agency:
HD33000/HD/NICHD NIH HHS; R01 HD050570/HD/NICHD NIH HHS; R01 HD050570-01A2/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Glucocorticoids; 0/Receptors, Glucocorticoid; 3XMK78S47O/Testosterone; 53-59-8/NADP; EC 1.1.1.146/11-beta-Hydroxysteroid Dehydrogenase Type 1
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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