Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum : possible implication in the metabolic syndrome

Senesi, Silvia and Legeza, Balázs and Balázs, Zoltán and Csala, Miklós and Marcolongo, Paola and Kereszturi, Eva and Szelényi, Péter and Egger, Christine and Fulceri, Rosella and Mandl, József and Giunti, Roberta and Odermatt, Alex and Bánhegyi, Gábor and Benedetti, Angelo. (2010) Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum : possible implication in the metabolic syndrome. Endocrinology, Vol. 151, H. 10. pp. 4830-4839.

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Official URL: http://edoc.unibas.ch/dok/A5841136

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Both fructose consumption and increased intracellular glucocorticoid activation have been implicated in the pathogenesis of the metabolic syndrome. Glucocorticoid activation by 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) depends on hexose-6-phosphate dehydrogenase (H6PD), which physically interacts with 11?-HSD1 at the luminal surface of the endoplasmic reticulum (ER) membrane and generates reduced nicotinamide adenine dinucleotide phosphate for the reduction of glucocorticoids. The reducing equivalents for the reaction are provided by glucose-6-phosphate (G6P) that is transported by G6P translocase into the ER. Here, we show that fructose-6-phosphate (F6P) can substitute for G6P and is sufficient to maintain reductase activity of 11?-HSD1 in isolated microsomes. Our findings indicate that the mechanisms of F6P and G6P transport across the ER membrane are distinct and provide evidence that F6P is converted to G6P in the ER lumen, thus yielding substrate for H6PD-dependent reduced nicotinamide adenine dinucleotide phosphate generation. Using the purified enzyme, we show that F6P cannot be directly dehydrogenated by H6PD, and we also excluded H6PD as a phosphohexose isomerase. Therefore, we postulate the existence of an ER luminal hexose-phosphate isomerase different from the cytosolic enzyme. The results suggest that cytosolic F6P promotes prereceptor glucocorticoid activation in white adipose tissue, which might have a role in the pathophysiology of the metabolic syndrome.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Legeza, Balazs and Balazs, Zoltan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:17
Deposited On:14 Sep 2012 06:37

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