In vitro, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD-1 is highly expressed in liver, where the reaction direction is 11beta-reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11beta-HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11beta-HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions. We have selectively repressed hepatic 11beta-HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11beta-HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in gluconeogenesis. Similar effects were seen after 3 weeks of oestradiol treatment. To examine whether this was due to any direct effect of oestradiol upon PEPCK, the experiment was repeated in adrenalectomised rats+/-glucocorticoid replacement. In adrenalectomised rats, oestradiol did not attenuate hepatic PEPCK, whilst glucocorticoid replacement restored this action. Oestradiol did not alter hepatic metabolism of corticosterone by pathways other than 11beta-HSD-1. These data suggest 11beta-HSD-1 plays an important role in maintaining expression of key glucocorticoid-regulated hepatic transcripts. Enzyme inhibition may provide a useful therapeutic target for manipulating glucose homeostasis.

This article has been cited by other articles:

				P. Barat, D. E. W. Livingstone, C. M. C. Elferink, C. R. McDonnell, B. R. Walker, and R. Andrew Effects of Gonadectomy on Glucocorticoid Metabolism in Obese Zucker Rats Endocrinology, October 1, 2007; 148(10): 4836 - 4843. [Abstract] [Full Text] [PDF]

				A. P. L. de Oliveira, H. V. Domingos, G. Cavriani, A. S. Damazo, A. L. dos Santos Franco, S. M. Oliani, R. M. Oliveira-Filho, B. B. Vargaftig, and W. T. de Lima Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol Am J Physiol Cell Physiol, September 1, 2007; 293(3): C1120 - C1128. [Abstract] [Full Text] [PDF]

				R. Basu, R. Singh, A. Basu, C.M. Johnson, and R. A. Rizza Effect of Nutrient Ingestion on Total-Body and Splanchnic Cortisol Production in Humans Diabetes, March 1, 2006; 55(3): 667 - 674. [Abstract] [Full Text] [PDF]

				P. G. Cohen and J. M. Holbrook Postmenopausal Asthma: The Estradiol 11{beta}-Hydroxysteroid Dehydrogenase Connection Arch Intern Med, December 13, 2004; 164(22): 2501 - 2501. [Full Text] [PDF]

				J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]

				M. Friedberg, E. Zoumakis, N. Hiroi, T. Bader, G. P. Chrousos, and Z.'e. Hochberg Modulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 385 - 393. [Abstract] [Full Text] [PDF]

				M. M. Vijayan, A. Takemura, and T. P. Mommsen Estradiol impairs hyposmoregulatory capacity in the euryhaline tilapia, Oreochromis mossambicus Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2001; 281(4): R1161 - R1168. [Abstract] [Full Text] [PDF]

				L. J. S. Williams, V. Lyons, I. MacLeod, V. Rajan, G. J. Darlington, V. Poli, J. R. Seckl, and K. E. Chapman C/EBP Regulates Hepatic Transcription of 11beta -Hydroxysteroid Dehydrogenase Type 1. A NOVEL MECHANISM FOR CROSS-TALK BETWEEN THE C/EBP AND GLUCOCORTICOID SIGNALING PATHWAYS J. Biol. Chem., September 22, 2000; 275(39): 30232 - 30239. [Abstract] [Full Text] [PDF]