Mechanism of repression of 11β-hydroxysteroid dehydrogenase type 1 by growth hormone in 3T3-L1 adipocytes.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P<0.05). 11β-HSD1 mRNA levels in cells treated with GH in the presence of 1 μM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 μM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 μM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 μM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11β-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I.
Department of Medicine II, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
Toko
T
Muraoka
Naomi
N
Hizuka
Izumi
I
Fukuda
Yukiko
Y
Ishikawa
Atsuhiro
A
Ichihara
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004794:Enzyme Repression / Q000187:drug effects; D013006:Growth Hormone / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D007328:Insulin; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D012333:RNA, Messenger; C519530:insulin-like growth factor-1, mouse; C404768:vatalanib; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D017526:Receptor, IGF Type 1