title: Metabolic Coupling Determines the Activity: Comparison of 11β-Hydroxysteroid Dehydrogenase 1 and Its Coupling between Liver Parenchymal Cells and Testicular Leydig Cells.
abstract: BACKGROUND
  11β-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.
  
  
  METHODS
  To 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.
  
  
  CONCLUSIONS
  G6P 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.
authors.affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Li
authors.affiliation: Research Academy of Reproductive Biomedicine, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
authors.affiliation: Research Academy of Reproductive Biomedicine, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Xiaoheng
authors.initials: X
authors.lastname: Li
authors.affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Yi-Yan
authors.initials: YY
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Hu
authors.affiliation: Research Academy of Reproductive Biomedicine, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, The Miriam Hospital, Brown University School of Medicine, Providence, RI 02906, United States of America.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Latif
authors.affiliation: Department of Pathology and Laboratory Medicine, The Miriam Hospital, Brown University School of Medicine, Providence, RI 02906, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morris
authors.affiliation: Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, Heilongjiang, PR China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Chu
authors.affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China; Research Academy of Reproductive Biomedicine, Wenzhou Medical University, Wenzhou, ZJ 325000, PR China; Population Council, 1230 York Avenue, New York, NY 10065, United States of America.
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006801:Humans; D007985:Leydig Cells / Q000166:cytology / Q000201:enzymology*; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017920:Antiporters; D003509:Cyclohexanecarboxylic Acids; D009004:Monosaccharide Transport Proteins; C113180:S 3483; C503531:SLC37A4 protein, human; C503533:Slc37a4 protein, rat; D009249:NADP; D019298:Glucose-6-Phosphate; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human