Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: possible implication in the metabolic syndrome.
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.
Senesi
Silvia
S
Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy.
Legeza
Balázs
B
Balázs
Zoltán
Z
Csala
Miklós
M
Marcolongo
Paola
P
Kereszturi
Eva
E
Szelényi
Péter
P
Egger
Christine
C
Fulceri
Rosella
R
Mandl
József
J
Giunti
Roberta
R
Odermatt
Alex
A
Bánhegyi
Gábor
G
Benedetti
Angelo
A
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
D005636:Fructosephosphates; D005938:Glucocorticoids; D009249:NADP; C027618:fructose-6-phosphate; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D003348:Cortisone