Abstract
Background11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) interconverts active 11β-hydroxyl glucocorticoids and inactive 11keto forms. However, its directionality is determined by availability of NADP+/NADPH. In liver cells, 11β-HSD1 behaves as a primary reductase, while in Leydig cells it acts as a primary oxidase. However, the exact mechanism is not clear. The direction of 11β-HSD1 has been proposed to be regulated by hexose-6-phosphate dehydrogenase (H6PDH), which catalyzes glucose-6-phosphate (G6P) to generate NADPH that drives 11β-HSD1 towards reduction.MethodologyTo examine the coupling between 11β-HSD1 and H6PDH, we added G6P to rat and human liver and testis or Leydig cell microsomes, and 11β-HSD1 activity was measured by radiometry.Results and ConclusionsG6P stimulated 11β-HSD1 reductase activity in rat (3 fold) or human liver (1.5 fold), but not at all in testis. S3483, a G6P transporter inhibitor, reversed the G6P-mediated increases of 11β-HSD1 reductase activity. We compared the extent to which 11β-HSD1 in rat Leydig and liver cells might be coupled to H6PDH. In order to clarify the location of H6PDH within the testis, we used the Leydig cell toxicant ethane dimethanesulfonate (EDS) to selectively deplete Leydig cells. The depletion of Leydig cells eliminated Hsd11b1 (encoding 11β-HSD1) expression but did not affect the expression of H6pd (encoding H6PDH) and Slc37a4 (encoding G6P transporter). H6pd mRNA level and H6PDH activity were barely detectable in purified rat Leydig cells. In conclusion, the availability of H6PDH determines the different direction of 11β-HSD1 in liver and Leydig cells.
Highlights
Glucocorticoids (GCs) have a wide range of physiological and pharmacological roles in mammalian functions [1, 2]
We compared the extent to which 11β-HSD1 in rat Leydig and liver cells might be coupled to hexose-6-phosphate dehydrogenase (H6PDH)
H6pd mRNA level and H6PDH activity were barely detectable in purified rat Leydig cells
Summary
Glucocorticoids (GCs) have a wide range of physiological and pharmacological roles in mammalian functions [1, 2]. Intracellular levels of GCs (corticosterone, CORT, in rats, and cortisol in humans) are regulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) that has two known isoforms, type I (11β-HSD1) and type II (11β-HSD2). 11β-HSD1 is an NADP+/NADPH dependent oxidoreductase, catalyzing the interconversion of 11β-hydroxyl steroids (CORT and cortisol) and 11-keto steroids (such as 11-dehydrocorticosterone, 11DHC, in rats, and cortisone in humans) and is most abundantly expressed in GC target tissues such as testis, liver, and fat [4]. 11βHSD1 is only expressed in the Leydig cell, which produces testosterone [5, 6]. The expression level of 11β-HSD1 in the rat Leydig cell is the highest among all cell types, and its level was about 4 fold higher than that in liver cells [7]. When a plasmid containing the entire coding region of 11β-HSD1 gene (Hsd11b1) was transiently transfected into two different cell lines, CHOP and COS1, oxidase activity was predominant in the former whereas reductase activity was higher in the latter [8]
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