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

Autor: Balázs Legeza, Angelo Benedetti, Roberta Giunti, Christine Egger, Paola Marcolongo, Gábor Bánhegyi, Miklós Csala, Péter Szelényi, Zoltán Balázs, József Mandl, Silvia Senesi, Rosella Fulceri, Éva Kereszturi, Alex Odermatt
Rok vydání: 2010
Předmět:
Male
LIVER MICROSOMAL VESICLES
Endocrinology
Diabetes and Metabolism
HEXOSE-6-PHOSPHATE DEHYDROGENASE
Clinical Biochemistry
Fructose 6-phosphate
Dehydrogenase
Endoplasmic Reticulum
Biochemistry
Rats
Sprague-Dawley
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
11-beta-Hydroxysteroid Dehydrogenase Type 1
GLUCOSE-6-PHOSPHATE TRANSPORT
Cells
Cultured
Metabolic Syndrome
INSULIN-RESISTANCE
0303 health sciences
Fructosephosphates
ADIPOSE-TISSUE
Adipose Tissue
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1
Microsomes
Liver
hormones
hormone substitutes
and hormone antagonists
Glucocorticoid
Intracellular
medicine.drug
medicine.medical_specialty
RAT-LIVER
Down-Regulation
VISCERAL ADIPOSITY
030209 endocrinology & metabolism
Biology
FRUCTOSE CONSUMPTION
03 medical and health sciences
Internal medicine
medicine
Animals
Humans
Glucocorticoids
030304 developmental biology
Nicotinamide
Endoplasmic reticulum
Biochemistry (medical)
Fructose
GLUCOSE
Rats
Cortisone
Glucose
chemistry
Microsome
NADP
030217 neurology & neurosurgery
Zdroj: Endocrinology
ISSN: 1945-7170
0013-7227
DOI: 10.1210/en.2010-0614
Popis: 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.
Databáze: OpenAIRE
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