Evidence for transcript-specific epigenetic regulation of glucocorticoid-stimulated skeletal muscle 11β-hydroxysteroid dehydrogenase-1 activity in type 2 diabetes

Clinical Epigenetics

Richard Saffery²  Christina Jang³  Varuni R Obeyesekere⁴  Warrick J Inder¹ 

[1] School of Medicine, University of Queensland, 288 Herston Road, Herston, QLD, 4006, Australia;Developmental Epigenetics, Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Flemington Road, Parkville, VIC, 3052, Australia;Centres for Health Research, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD, 4102, Australia;Department of Endocrinology and Diabetes, St Vincent’s Hospital, 41 Victoria Parade, Fitzroy, VIC 3065, Australia

关键词: DNA methylation;    Epigenetics;    Diabetes;    Cortisol;    11β-Hydroxysteroid dehydrogenase-1;   

Others  :  791151
DOI  :  10.1186/1868-7083-4-24

 received in 2012-08-16, accepted in 2012-11-12,  发布年份 2012

【 摘 要 】

Background

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol in insulin target tissues. In people with type 2 diabetes, skeletal muscle (SkM) 11βHSD1 is upregulated by the potent glucocorticoid dexamethasone. The HSD11B1 gene has two promoters designated P1 and P2. CCAAT/enhancer-binding protein beta (C/EBPβ) is known to regulate expression of 11βHSD1 via the P2 promoter. In this study, we investigated the potential role of altered DNA methylation of the P1 and P2 promoters in the observed dexamethasone-induced upregulation of SkM 11βHSD1 oxoreductase activity in human diabetic subjects. SkM biopsies from 15 people with type 2 diabetes were collected before and after treatment with oral dexamethasone 4 mg/day for 4 days and SkM 11βHSD1, C/EBPβ and P1 and P2 promoter region mRNA levels were measured by quantitative RT-PCR. 11βHSD1 oxoreductase activity was quantified by measuring the conversion of radiolabeled ³H-cortisone to cortisol by thin layer chromatography. Analysis of HSD11B1 promoter methylation (P1 and P2) was performed using Sequenom MassARRAY EpiTYPER analysis.

Results

Dexamethasone treatment resulted in a significant increase in 11βHSD1 mRNA levels (P = 0.003), oxoreductase activity (P = 0.017) and C/EBPβ mRNA (P = 0.015), and increased expression of both the P1 (P = 0.008) and P2 (P = 0.016) promoter regions . The distal P1 promoter region showed a significant reduction in methylation following dexamethasone (P = 0.026). There was a significant negative correlation between the change in methylation at this site and the increment in 11βHSD1 oxoreductase activity (r = −0.62, P = 0.014).

Conclusions

Our findings of reduced methylation in the HSD11B1 P1 promoter in association with increased 11βHSD1 oxoreductase activity implicate complex multi-promoter epigenetic mechanisms in the regulation of 11βHSD1 levels in SkM.

【 授权许可】

   
2012 Inder et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM: 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 2004, 25:831-866.
• [2]Stewart PM: 11β-Hydroxysteroid dehydrogenase: implications for clinical medicine. Clin Endocrinol (Oxf) 1996, 44:493-499.
• [3]Draper N, Stewart PM: 11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action. J Endocrinol 2005, 186:251-271.
• [4]DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J: Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985, 76:149-155.
• [5]Jang C, Obeyesekere VR, Dilley RJ, Krozowski Z, Inder WJ, Alford FP: Altered activity of 11β-hydroxysteroid dehydrogenase types 1 and 2 in skeletal muscle confers metabolic protection in subjects with type 2 diabetes. J Clin Endocrinol Metab 2007, 92:3314-3320.
• [6]Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD: Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 2002, 51:1066-1075.
• [7]Hammami MM, Siiteri PK: Regulation of 11β-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab 1991, 73:326-334.
• [8]Sun K, Myatt L: Enhancement of glucocorticoid-induced 11β-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 2003, 144:5568-5577.
• [9]Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect ‘Cushing’s disease of the omentum’? Lancet 1997, 349:1210-1213.
• [10]Sun K, He P, Yang K: Intracrine induction of 11β-hydroxysteroid dehydrogenase type 1 expression by glucocorticoid potentiates prostaglandin production in the human chorionic trophoblast. Biol Reprod 2002, 67:1450-1455.
• [11]Yang Z, Guo C, Zhu P, Li W, Myatt L, Sun K: Role of glucocorticoid receptor and CCAAT/enhancer-binding protein alpha in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts. J Endocrinol 2007, 195:241-253.
• [12]Gout J, Tirard J, Thevenon C, Riou JP, Begeot M, Naville D: CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11β-hydroxysteroid dehydrogenase encoding gene in adipose cells. Biochimie 2006, 88:1115-1124.
• [13]Sai S, Esteves CL, Kelly V, Michailidou Z, Anderson K, Coll AP, Nakagawa Y, Ohzeki T, Seckl JR, Chapman KE: Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-beta. Mol Endocrinol 2008, 22:2049-2060.
• [14]Bruley C, Lyons V, Worsley AG, Wilde MD, Darlington GD, Morton NM, Seckl JR, Chapman KE: A novel promoter for the 11β-hydroxysteroid dehydrogenase type 1 gene is active in lung and is C/EBPα independent. Endocrinology 2006, 147:2879-2885.
• [15]Williams LJ, Lyons V, MacLeod I, Rajan V, Darlington GJ, Poli V, Seckl JR, Chapman KE: C/EBP regulates hepatic transcription of 11β-hydroxysteroid dehydrogenase type 1. A novel mechanism for cross-talk between the C/EBP and glucocorticoid signaling pathways. J Biol Chem 2000, 275:30232-30239.
• [16]Yang H, Mammen J, Wei W, Menconi M, Evenson A, Fareed M, Petkova V, Hasselgren PO: Expression and activity of C/EBPbeta and delta are upregulated by dexamethasone in skeletal muscle. J Cell Physiol 2005, 204:219-226.
• [17]Foley DL, Craig JM, Morley R, Olsson CA, Dwyer T, Smith K, Saffery R: Prospects for epigenetic epidemiology. Am J Epidemiol 2009, 169:389-400.
• [18]Kangaspeska S, Stride B, Metivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G: Transient cyclical methylation of promoter DNA. Nature 2008, 452:112-115.
• [19]Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G: Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008, 452:45-50.
• [20]Rakyan VK, Beyan H, Down TA, Hawa MI, Maslau S, Aden D, Daunay A, Busato F, Mein CA, Manfras B, Dias KR, Bell CG, Tost J, Boehm BO, Beck S, Leslie RD: Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 2011, 7:e1002300.
• [21]Zilberfarb V, Siquier K, Strosberg AD, Issad T: Effect of dexamethasone on adipocyte differentiation markers and tumour necrosis factor-alpha expression in human PAZ6 cells. Diabetologia 2001, 44:377-386.
• [22]Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM: Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest 2004, 114:1146-1157.
• [23]Friso S, Pizzolo F, Choi SW, Guarini P, Castagna A, Ravagnani V, Carletto A, Pattini P, Corrocher R, Olivieri O: Epigenetic control of 11β-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis 2008, 199:323-327.
• [24]Barres R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, Krook A, Zierath JR: Non-CpG methylation of the PGC-1.alpha; promoter through DNMT3B controls mitochondrial density. Cell Metab 2009, 10:189-198.
• [25]Brons C, Jacobsen S, Nilsson E, Ronn T, Jensen CB, Storgaard H, Poulsen P, Groop L, Ling C, Astrup A, Vaag A: Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weight-dependent manner. J Clin Endocrinol Metab 2010, 95:3048-3056.
• [26]Jang C, Obeyesekere VR, Dilley RJ, Alford FP, Inder WJ: 11Beta hydroxysteroid dehydrogenase type 1 is expressed and is biologically active in human skeletal muscle. Clin Endocrinol (Oxf) 2006, 65:800-805.
• [27]Levy JC, Matthews DR, Hermans MP: Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998, 21:2191-2192.
• [28]Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, Cantor CR, Field JK, van den Boom D: Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A 2005, 102:15785-15790.
• [29]Wong N, Morley R, Saffery R, Craig J: Archived Guthrie blood spots as a novel source for quantitative DNA methylation analysis. Biotechniques 2008, 45:423-424. 426, 428, passim