Contribution of Fructose-6-Phosphate to Glucocorticoid Activation in the Endoplasmic Reticulum: Possible Implication in the Metabolic Syndrome

• Published in: Endocrinology (Philadelphia) 2010-10, Vol.151 (10), p.4830-4839
• Main Authors: Senesi, Silvia, Legeza, Balázs, Balázs, Zoltán, Csala, Miklós, Marcolongo, Paola, Kereszturi, Éva, Szelényi, Péter, Egger, Christine, Fulceri, Rosella, Mandl, József, Giunti, Roberta, Odermatt, Alex, Bánhegyi, Gábor, Benedetti, Angelo
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - physiology; 11β-Hydroxysteroid dehydrogenase; Adenine; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Biological and medical sciences; Cells, Cultured; Cortisone - metabolism; Dehydrogenase; Dehydrogenases; Dehydrogenation; Down-Regulation - drug effects; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzymes; Fructose; Fructose-6-phosphate; Fructosephosphates - metabolism; Fructosephosphates - pharmacology; Fundamental and applied biological sciences. Psychology; Glucocorticoids; Glucocorticoids - metabolism; Glucose - metabolism; Hexose; Humans; Hydroxysteroids; Male; Medical sciences; Membranes; Metabolic diseases; Metabolic disorders; Metabolic rate; Metabolic syndrome; Metabolic Syndrome - etiology; Metabolic Syndrome - metabolism; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Miscellaneous; NADP - metabolism; NADPH-diaphorase; Nicotinamide; Nicotinamide adenine dinucleotide; Other metabolic disorders; Pathogenesis; Phosphates; Rats; Rats, Sprague-Dawley; Reductases; Translocase; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0614

Both fructose consumption and increased intracellular glucocorticoid activation have been implicated in the pathogenesis of the metabolic syndrome. Glucocorticoid activation by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) depends on hexose-6-phosphate dehydrogenase (H6PD), which physically interacts with 11β-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 11β-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. Fructose-6-phosphate can be converted to glucose-6-phosphate in the lumen of the endoplasmic reticulum and hence can drive local glucocorticoid activation by providing the hexose-6-phosphate dehydrogenase – 11β-hydroxysteroid dehydrogenase type 1 system with reducing power.