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The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11ß-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue

Department of Pathophysiology, Experimental Medicine, and Public Health (P.M., S.P., S.S., R.F., G.B., A.B.), University of Siena, Siena 53100, Italy; Department of Medical Chemistry, Molecular Biology, and Pathobiochemistry (J.M., G.B.), Semmelweis University, and Endoplasmic Reticulum Research Group (L.W., J.M., G.B.), Hungarian Academy of Sciences, H-1088 Budapest, Hungary; and Laboratoire de Chimie Physiologique (I.G.), Universite Catholique de Louvain, B-1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Gábor Bánhegyi, Dipartimento di Fisiopatologia, Medicina Sperimentale e Sanità Pubblica, Via A. Moro no. 1, 53100 Siena, Italy. E-mail: banhegyi{at}unisi.it.

11ß-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 11ß-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-11ß-hydroxysteroid dehydrogenase type 1 system and indicate that all three components are potential pharmacological targets for modulating local glucocorticoid activation.

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