The glucose-6-phosphate transporter-hexose-6-phosphate dehydrogenase-11beta-hydroxysteroid dehydrogenase type 1 system of the adipose tissue.
11beta-hydroxysteroid dehydrogenase type 1, expressed mainly in the endoplasmic reticulum of adipocytes and hepatocytes, plays an important role in the prereceptorial activation of glucocorticoids. In liver endoplasmic reticulum-derived microsomal vesicles, nicotinamide adenine dinucleotide phosphate reduced supply to the enzyme is guaranteed by a tight functional connection with hexose-6-phosphate dehydrogenase and the glucose-6-phosphate transporter (G6PT). In adipose tissue, the proteins and their activities supporting the action of 11beta-hydroxysteroid dehydrogenase type 1 have not been explored yet. Here we report the occurrence of the hexose-6-phosphate dehydrogenase in rat epididymal fat, as detected at the level of mRNA, protein, and activity. In the isolated microsomes, the activity was evident only on the permeabilization of the membrane because of the poor permeability to the cofactor nicotinamide adenine dineucleotide phosphate (NADP(+)), which is consistent with the intralumenal compartmentation of both the enzyme and a pool of pyridine nucleotides. In fat cells, the access of the substrate, glucose-6-phosphate to the intralumenal hexose-6-phosphate dehydrogenase appeared to be mediated by the liver-type G6PT. In fact, the G6PT expression was revealed at the level of mRNA and protein. Accordingly, the transport of glucose-6-phosphate was demonstrated in microsomal vesicles, and it was inhibited by S3483, a prototypic inhibitor of G6PT. Furthermore, isolated adipocytes produced cortisol on addition of cortisone, and the production was markedly inhibited by S3483. The results show that adipocytes are equipped with a functional G6PT-hexose-6-phosphate dehydrogenase-11beta-hydroxysteroid dehydrogenase type 1 system and indicate that all three components are potential pharmacological targets for modulating local glucocorticoid activation.
Marcolongo
Paola
P
Department of Pathophysiology, University of Siena, 53100 Siena, Italy.
Piccirella
Simona
S
Senesi
Silvia
S
Wunderlich
Livius
L
Gerin
Isabelle
I
Mandl
József
J
Fulceri
Rosella
R
Bánhegyi
Gábor
G
Benedetti
Angelo
A
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004822:Epididymis / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D017920:Antiporters; D003509:Cyclohexanecarboxylic Acids; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C113180:S 3483; C111261:glucose 6-phosphate(transporter); D019298:Glucose-6-Phosphate; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone