Ceramide and adenosine 5'-monophosphate-activated protein kinase are two novel regulators of 11beta-hydroxysteroid dehydrogenase type 1 expression and activity in cultured preadipocytes.
Increased activity of intracellular glucocorticoid reactivating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in obese adipose tissue contributes to adipose dysfunction. As recent studies have highlighted a potential role of preadipocytes in adipose dysfunction, we tested the hypothesis that a variety of metabolic stress mediated by ceramide or AMP-activated protein kinase (AMPK) would regulate 11beta-HSD1 in preadipocytes. The present study is the first to show that 1) expression of 11beta-HSD1 in 3T3-L1 preadipocytes was robustly induced when cells were treated with cell-permeable ceramide analogue C(2) ceramide, bacterial sphingomyelinase, and sphingosine 1-phosphate, 2) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced activation of AMPK augmented the expression and enzyme activity of 11beta-HSD1, and 3) these results were reproduced in human preadipocytes. We demonstrate for the first time that C(2) ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) beta and its binding to 11beta-HSD1 promoter. Transient knockdown of C/EBPbeta protein by small interfering RNA markedly attenuated the expression of 11beta-HSD1 induced by C(2) ceramide or AICAR. The present study provides novel evidence that ceramide- and AMPK-mediated signaling pathways augment the expression and activity of 11beta-HSD1 in preadipocytes by way of C/EBPbeta, thereby highlighting a novel, metabolic stress-related regulation of 11beta-HSD1 in a cell-specific manner.
Arai
N
N
Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masuzaki
H
H
Tanaka
T
T
Ishii
T
T
Yasue
S
S
Kobayashi
N
N
Tomita
T
T
Noguchi
M
M
Kusakabe
T
T
Fujikura
J
J
Ebihara
K
K
Hirata
M
M
Hosoda
K
K
Hayashi
T
T
Sawai
H
H
Minokoshi
Y
Y
Nakao
K
K
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism*; D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D009097:Multienzyme Complexes / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D022782:CCAAT-Enhancer-Binding Protein-beta; D002518:Ceramides; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide