title: Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: possible implication in the metabolic syndrome.
abstract: 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.
authors.affiliation: Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Senesi
authors.forename: Balázs
authors.initials: B
authors.lastname: Legeza
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Balázs
authors.forename: Miklós
authors.initials: M
authors.lastname: Csala
authors.forename: Paola
authors.initials: P
authors.lastname: Marcolongo
authors.forename: Eva
authors.initials: E
authors.lastname: Kereszturi
authors.forename: Péter
authors.initials: P
authors.lastname: Szelényi
authors.forename: Christine
authors.initials: C
authors.lastname: Egger
authors.forename: Rosella
authors.initials: R
authors.lastname: Fulceri
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.forename: Roberta
authors.initials: R
authors.lastname: Giunti
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
authors.forename: Angelo
authors.initials: A
authors.lastname: Benedetti
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003348:Cortisone / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D005636:Fructosephosphates / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005636:Fructosephosphates; D005938:Glucocorticoids; D009249:NADP; C027618:fructose-6-phosphate; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D003348:Cortisone