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Review

11β-Hydroxysteroid dehydrogenase Type 1 as a novel therapeutic target in metabolic and neurodegenerative disease

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Pages 771-783 | Published online: 02 Mar 2005

Bibliography

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  • •A comprehensive review of the history of 11HSD research.
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  • •A short review laying out the key evidence in support of the role of 11HSD1 in modulating glucocorticoid receptor activation.
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  • •This paper contained the original description of the predominant reductase activity of 11HSD1 in adipose tissue, and the hypothesis that this activity might be increased in obesity.
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  • ••This paper provided the first evidencethat 11HSD1 is a predominant reductase In the CNS and that its inhibition is potentially neuroprotective.
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  • DRAPER N, WALKER EA, BUJALSKA IJ et al: Mutations in the genes encoding 1 113-hydroxysteroid dehydrogenase Type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat. Genet. (2003) 34:434–439.
  • •The intriguing hypothesis that hexose-6-phosphate dehydrogenase (H6PDH) provides cofactor NADPH for 11HSD1 reductase is supported by this paper.
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  • ••This paper supports the potent influence ofadipose 11HSD1 on obesity and features of the metabolic syndrome.
  • PATERSON JM, HOLMES MC, MORTON NM, SECKL JR, MULLINS JJ: Liver-specific over-expression of 1113-HSD1 in transgenic mice produces insulin resistance, hyperlipidaemia and fatty liver. Proc. Endo. 2002(2002) P2-319. Abstract.
  • KOTELEVTSEV YV, HOLMES MC, BURCHELL A et al.:1113-Hydroxysteroid dehydrogenase Type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress. Proc. Nati Acad. Sri. USA (1997) 94:14924–14929.
  • •This paper is the first in a series concerning 11HSD1 I- mice, and provides proof-of-principle that loss of 11HSD1 is beneficial for the features of the metabolic syndrome.
  • HARRIS HJ, KOTELEVTSEV YV, MULLINS JJ, SECKL JR, HOLMES MC: 1113-Hydroxysteroid dehydrogenase Type 1 null mice have altered hypothalamic-pituitary-adrenal axis activity: a novel control of glucocorticoid feedback. Endocrinology (2001) 142:114–120.
  • MORTON NM, HOLMES MC, FIEVET C et al.: Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 1113-hydroxysteroid dehydrogenase Type 1 null mice. Biol Chem. (2001) 276:41293–41300.
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  • •This paper shows the influence of adipose 11HSD1 on blood pressure, an effect apparently mediated by increased adipose angiotensinogen production. However, other studies in humans do not suggest that this mechanism is necessarily relevant in man.
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  • ••This is a key paper in understanding theInfluence of 11HSD1 on cognitive function.
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  • ••This is the first in a series of papersdocumenting increased subcutaneous adipose 11HSD1 in human obesity.
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  • •This is a key paper from which much of the authors' further work originated. The data showed that inhibition of 11HSD1 enhanced 'whole body' insulin sensitivity, an effect confirmed by later studies as being mediated by enhanced hepatic insulin sensitivity.
  • ANDREWS RC, ROOYACKERS O, WALKER BR: Effects of the 1 113-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with Type 2 diabetes. I Clin. Endocrinol. Metab. (2003) 88:285–291.
  • LIVINGSTONE DE, WALKER BR: Is 1113-hydroxysteroid dehydrogenase Type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. J. Marmara Exp. Ther. (2003) 305:167–172.
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  • SANDEEP TC, MACLULLICH AM, YAU JL et al.:1113-Hydroxysteroid dehydrogenase Type 1 is expressed in human brain: inhibition with carbenoxolone improves cognitive function in healthy elderly men. Endocr. Abstr. (2002) 3:0C41. Abstract.
  • BARF T, VALLGARDA J, EMOND R et al.: Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 1113-hydroxysteroid dehydrogenase Type 1. J. Med. Chem. (2002) 45:3813–3815.
  • ALBERTS P, ENGBLOM L, EDLING N et al: Selective inhibition of 1113-hydroxysteroid dehydrogenase Type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia (2002) 45:1528–1532.
  • ••This paper describes the metabolic benefitsof the first 11ESD1-selectiye inhibitors, the arylsulphonamidothiazoles, in mice.
  • HUNDERTMARK S, DILL A, EBERT A et al: Foetal lung maturation in 1113-hydroxysteroid dehydrogenase Type 1 knockout mice. Horm. Metab. Res. (2002) 34:545–549.
  • HUNDERTMARK S, DILL A, BUHLER H et al.: 1113-hydroxysteroid dehydrogenase Type 1: a new regulator of fetal lung maturation. Horm. Metab. Res. (2002) 34:537–544.
  • HAD OKE PW, CHRISTY C, KOTELEVTSEV YV et al.: Endothelial cell dysfunction in mice after transgenic knockout of Type 2, but not Type 1, 1113-hydroxysteroid dehydrogenase. Circulation (2001) 104:2832–2837.
  • COOPER MS, BUJALSKA I, RABBITT E, WALKER EA, BLAND R, SHEPPARD MC: Modulation of 11 [131-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. Bone !Winer. Res. (2001) 16:1037–1044.
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  • TETSUKA M, HAINES LC, MILNE M, SIMPSON GE, HILLIER SG: Regulation of 11(3-hydroxysteroid dehydrogenase Type 1 gene expression by LH and interleukin-1(3 in cultured rat granulosa cells. J. Endocrinol (1999) 163:417–423.
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  • SOUNESS GW, LATIF SA, LAURENZO JL, MORRIS DJ: 11 a- and 11(3-hydroxyprogesterone, potent inhibitors of 11(3-hydroxysteroid dehydrogenase (isoforms 1 and 2), confer marked mineralocorticoid activity on corticosterone in the ADX rat. Endocrinology (1995) 136: 1809-1812.
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