Dr Dawn Livingstone
Steroid hormone signalling has a potent influence on fuel metabolism and body fat distribution. The action of steroids is determined via ligand-receptor interaction, but this is modulated within target tissues by pre-receptor metabolism. My research has several broad strands woven around this central theme.
- 2014 - present: Lecturer, University of Edinburgh
- 2005 - 2014: Research Fellow, Centre for Cardiovascular Science, University of Edinburgh
- 2000 - 2005: Research Fellow, Department of Medicine, University of Edinburgh
- 2000: PhD Medical Sciences, University of Edinburgh
- 1996: BSc (Hons) Pharmacology, University of Edinburgh
Glucocorticoid metabolism and metabolic risk:
The enzyme 5α-reductase 1 is the rate limiting step in A-ring reduction of glucocorticoids, and also metabolises other steroid hormones. 5α-reductase 1 is localised in metabolically active tissues, such as liver and fat, where it can therefore alter steroid metabolite profile.
We have recently demonstrated that whole body disruption of 5α-reductase, by either transgenic manipulation or pharmacological inhibition, results in the development of metabolic risk factors such as loss of insulin sensitivity and accumulation of liver fat.
We are now working towards defining the systems involved in effecting these metabolic outcomes.
5α-reductase is also expressed in the brain, where, in addition to catalysing glucocorticoid metabolism, it controls production of neuro-steroids.
We are currently determining the central effects of disrupted 5α-reductase in terms of metabolism and behaviour.
Development of selective glucocorticoid receptor modulators:
Glucocorticoid steroids are widely prescribed for their potent anti-inflammatory effects, but their use is limited by adverse effects on metabolism.
There is therefore a need for more selective anti-inflammatory steroids, with an improved therapeutic index.
The glucocorticoid product of A-ring reduction is 3α,5α-tetrahydrocorticosterone (5α-THB). We have demonstrated biological activity of this metabolite, and identified it as a “dissociated glucocorticoid” whereby it retains some, but not all, glucocorticoid activity.
We are currently evaluating the efficacy and side effect profile of 5α-THB in inflammation, particularly for topical administration in conditions such as eczema.
- Amber Abernethy
- Dr Nyo Nyo Tun
Safer topical treatment for inflammation using 5α-tetrahydrocorticosterone in mouse models. Gastaldello A, Livingstone DE, Abernethie AJ, Tsang N, Walker BR, Hadoke PW, Andrew R. Biochem Pharmacol. 2017 Jan 24. pii: S0006-2952(17)30038-2. doi: 10.1016/j.bcp.2017.01.008. [Epub ahead of print]
Spatial Localization and Quantitation of Androgens in Mouse Testis by Mass Spectrometry Imaging. Cobice DF*, Livingstone DE*, Mackay CL, Goodwin RJ, Smith LB, Walker BR, Andrew R. Anal Chem. 2016 Oct 14. PMID: 27676129 * joint 1st author
Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus. Anderson AJ, Andrew R, Homer NZ, Jones GC, Smith K, Livingstone DE, Walker BR, Stimson RH. J Clin Endocrinol Metab. 2016 Oct;101(10):3787-3793. PMID: 27459533
Metabolic dysfunction in female mice with disruption of 5α-reductase 1. Livingstone DE, Di Rollo EM, Mak TC, Sooy K, Walker BR, Andrew R. J Endocrinol. 2016 Sep 19. pii: JOE-16-0125. [Epub ahead of print] PMID: 27647861
ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy. Nixon M, Mackenzie SD, Taylor AI, Homer NZ, Livingstone DE, Mouras R, Morgan RA, Mole DJ, Stimson RH, Reynolds RM, Elfick AP, Andrew R, Walker BR. Sci Transl Med. 2016 Aug 17;8(352):352ra109. doi: 10.1126/scitranslmed.aaf9074. PMID: 27535620
Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men. Gibb FW, Homer NZ, Faqehi AM, Upreti R, Livingstone DE, McInnes KJ, Andrew R, Walker BR. J Clin Endocrinol Metab. 2016 May;101(5):2040-6. doi: 10.1210/jc.2015-4146. Epub 2016 Mar 11. PMID: 26967690
Livingstone, D. E., Barat, P., Di Rollo, E. M., Rees, G. A., Weldin, B. A., Rog-Zielinska, E. A., MacFarlane, D. P., Walker, B. R., Andrew, R. (2015). 5α-Reductase Type 1 Deficiency or Inhibition Predisposes to Insulin Resistance, Hepatic Steatosis, and Liver Fibrosis in Rodents. Diabetes. 64(2):447-58.
Goedecke JH, Chorell E, Livingstone DE, Stimson RH, Hayes P, Adams K, Dave JA, Victor H, Levitt NS, Kahn SE, Seckl JR, Walker BR, Olsson T (2014) Glucocorticoid receptor gene expression in adipose tissue and associated metabolic risk in black and white South African women. International Journal of Obesity, 39(2):303-11.
Livingstone DE, Di Rollo EM, Yang C, Codrington LE, Mathews JA, Kara MA, Kenyon CJ, Walker BR, Andrew R (2014) Impaired clearance of glucocorticoids by 5α-reductase1 induces relative ‘adrenal insufficiency’ in mice. Journal of Endocrinology, 222, 257-66.
Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Marshall I, Stewart LH, Walker BR, Andrew R (2104) 5α-Reductase type 1 modulates insulin sensitivity in men. Journal of Clinical Endocrinology and Metabolism, 99, E1397-406.
Kipari T, Hadoke PW, Iqbal J, Man TY, Miller E, Coutinho AE, Zhang Z, Sullivan KM, Mitic T, Livingstone DE, Schrecker C, Samuel K, White CI, Bouhlel MA, Chinetti-Gbaguidi G, Staels B, Andrew R, Walker BR, Savill JS, Chapman KE, Seckl JR (2013). 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis. FASEB Journal, 27, 1519-31.
Wilson KS, Matrone G, Livingstone DE, Al-Dujaili EA, Mullins JJ, Tucker CS, Hadoke PW, Kenyon CJ, Denvir MA (2013). Physiological roles of glucocorticoids during early embryonic development of the zebrafish (Danio rerio). Journal of Physiology, 591, 6209-20.
Cottrell EC, Holmes MC, Livingstone DE, Kenyon CJ, Seckl J (2012). Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB Journal, 26, 1866-74.
Nixon M, Wake DJ, Livingstone DE, Stimson RH, Esteves CL, Seckl JR, Chapman KE, Andrew R, Walker BR (2012). Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. Diabetes, 61,790-6.
Evans LC, Livingstone DE, Kenyon CJ, Jansen MA, Dear JW, Mullins JJ, Bailey MA (2012). A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice. American Journal of Physiology: Renal Physiology, 303, F494-502.
Macfarlane DP, Zou X, Andrew R, Morton NM, Livingstone DE, Aucott RL, Nyirenda MJ, Iredale JP, Walker BR (2011). Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis. American Journal of Physiololgy: Endocrinology and Metabolism, 300, E402-9.
Bailey MA, Craigie E, Livingstone DE, Kotelevtsev YV, Al-Dujaili EA, Kenyon CJ, Mullins JJ (2011). Hsd11b2 Haploinsufficiency in Mice Causes Salt Sensitivity of Blood Pressure. Hypertension, 57, 515-20.
Yang C, Nixon M, Kenyon CJ, Livingstone DE, Duffin R, Rossi AG, Walker BR, Andrew R (2011). 5α-reduced glucocorticoids exhibit dissociated anti-inflammatory and metabolic effects. British Journal of Pharmacology, 164, 1661-71.
Goedecke JH, Evans J, Keswell D, Stimson RH, Livingstone DE, Hayes P, Adams K, Dave JA, Victor H, Levitt NS, Lambert EV, Walker BR, Seckl JR, Olsson T, Kahn SE (2011). Reduced gluteal expression of adipogenic and lipogenic genes in Black South African women is associated with obesity-related insulin resistance. Journal of Clinical Endocrinolology and Metabolism, 96, E2029-33.
McNeilly AD, Macfarlane DP, O'Flaherty E, Livingstone DE, Miti? T, McConnell KM, McKenzie SM, Davies E, Reynolds RM, Thiesson HC, Skøtt O, Walker BR, Andrew R (2010). Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice. Journal of Hepatology, 52, 705-11.
Livingstone DE, Grassick SL, Currie GL, Walker BR, Andrew R (2009). Dysregulation of glucocorticoid metabolism in murine obesity: comparable effects of leptin resistance and deficiency. Journal of Endocrinology, 201, 211-218.
Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity (2007). Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, Andrew R, Yki-Jarvenen H, Olsson T, Walker BR. Clinical Endocrinology (Oxford), 66, 440-446.
Livingstone DE*, Barat P*, Elferink C, McDonnell CR, Walker BR, Andrew R (2007). Effects of gonadectomy on glucocorticoid metabolism in obese Zucker rats. Endocrinology, 148, 4836-4483. *= joint first author
Livingstone DE, McInnes KJ, Walker BR, Andrew R (2005). Enhanced hepatic A-ring reduction of glucocorticoids in obesity: regulation by glucocorticoids and insulin. Obesity Research, 13, 1523-1526.
Drake AJ, Livingstone DE, Andrew R, Seckl JR, Morton NM, Walker BR (2005). Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feding in Wistar rats. Endocrinology, 146, 913-919.