PMID- 15956339
OWN - NLM
STAT- MEDLINE
DCOM- 20051004
LR  - 20061115
IS  - 0952-5041 (Print)
IS  - 0952-5041 (Linking)
VI  - 34
IP  - 3
DP  - 2005 Jun
TI  - Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 
      beta-hydroxysteroid dehydrogenase type 1.
PG  - 675-84
AB  - Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert 
      active cortisol and inactive cortisone. 11 beta-HSD2 (renal) acts only as a 
      dehydrogenase, converting cortisol to cortisone. 11 beta-HSD1 (liver) is a 
      bi-directional enzyme in cell homogenates, whereas in intact cells it typically 
      displays oxo-reductase activity, generating cortisol from cortisone. We recently 
      established that cortisone reductase deficiency is a digenic disease requiring 
      mutations in both the gene encoding 11 beta-HSD1 and in the gene for a novel 
      enzyme located within the lumen of the endoplasmic reticulum (ER), 
      hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the 
      co-factor required for oxo-reductase activity. Therefore, we hypothesized that 
      H6PDH expression may be an important determinant of 11 beta-HSD1 oxo-reductase 
      activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 
      beta-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase 
      activities in intact cells. Co-transfection of 11 beta-HSD1 with H6PDH increased 
      oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In 
      contrast, H6PDH had no effect on reaction direction of 11 beta-HSD2, nor did the 
      cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 beta-HSD1 
      oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 
      beta-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 beta-HSD1 oxo-reductase 
      activity whilst simultaneously increasing 11 beta-HSD1 dehydrogenase activity. In 
      human omental preadipocytes obtained from 15 females of variable body mass index 
      (BMI), H6PDH mRNA levels positively correlated with 11 beta-HSD1 oxo-reductase 
      activity, independent of 11 beta-HSD1 mRNA levels. H6PDH expression increased 
      5.3-fold across adipocyte differentiation (P < 0.05) and was associated with a 
      switch from 11 beta-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, 
      H6PDH is a crucial determinant of 11 beta-HSD1 oxo-reductase activity in intact 
      cells. Through its interaction with 11 beta-HSD1, H6PDH may represent a novel 
      target in the pathogenesis and treatment of obesity.
FAU - Bujalska, Iwona J
AU  - Bujalska IJ
AD  - Division of Medical Sciences, Endocrinology, Institute of Biomedical Research, 
      Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
FAU - Draper, Nicole
AU  - Draper N
FAU - Michailidou, Zoi
AU  - Michailidou Z
FAU - Tomlinson, Jeremy W
AU  - Tomlinson JW
FAU - White, Perrin C
AU  - White PC
FAU - Chapman, Karen E
AU  - Chapman KE
FAU - Walker, Elizabeth A
AU  - Walker EA
FAU - Stewart, Paul M
AU  - Stewart PM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Mol Endocrinol
JT  - Journal of molecular endocrinology
JID - 8902617
RN  - 0 (DNA Primers)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.1.- (Carbohydrate Dehydrogenases)
RN  - EC 1.1.1.- (galactose-6-phosphate dehydrogenase)
RN  - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 1)
SB  - IM
MH  - 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics/*metabolism
MH  - Adult
MH  - Animals
MH  - Base Sequence
MH  - Blotting, Western
MH  - CHO Cells
MH  - Carbohydrate Dehydrogenases/genetics/*metabolism
MH  - Cricetinae
MH  - DNA Primers
MH  - Female
MH  - Humans
MH  - Polymerase Chain Reaction
MH  - RNA, Messenger/genetics
MH  - RNA, Small Interfering/genetics
EDAT- 2005/06/16 09:00
MHDA- 2005/10/05 09:00
CRDT- 2005/06/16 09:00
PHST- 2005/06/16 09:00 [pubmed]
PHST- 2005/10/05 09:00 [medline]
PHST- 2005/06/16 09:00 [entrez]
AID - 34/3/675 [pii]
AID - 10.1677/jme.1.01718 [doi]
PST - ppublish
SO  - J Mol Endocrinol. 2005 Jun;34(3):675-84. doi: 10.1677/jme.1.01718.