My research group focuses on a range integrative physiology and biomedical questions and problems, which include:
- Investigating the pre-receptor regulation of glucocorticoid action in health and disease.
- Identifying the pathway fluxes of molecules involved in adaptive homeostasis within skeletal muscle.
- Indentifying the adaptive responses and pathways to stress, such as exercise and nutrient availability, in skeletal muscle.
We use a range of systems, molecular and genetic approaches with the end-points of our research being both basic- the what, how and why, and translational- the ultimately utility of the basic research to human health.
Our research group
Hexose-6-phosphate dehydrogenase (H6PDH) and the control of skeletal muscle glucose trafficking in metabolism
Following on from our discovery of inactivating H6PDH mutations in humans, and the analysis of a H6PDH knockout mouse, we have identified a mechanism by which intracellular glucocorticoid metabolism is dependent upon the flux of glucose-6-phosphate into the ER to generate the redox conditions that permit the enzyme 11β-hydroxysteroied dehydrogenase type 1 to function in the endoplasmic reticulum. When H6PDH is deficient ‘Apparent’ cortisone reductase deficiency ensues activating the HPA axis and driving adrenal androgen production, which in humans presents as premature puberty and PCOS in women. In mice we have observed a severe myopathy, driven by ER stress and the unfolded protein response, but we do not understand the molecular process involved that initiate this response. We wish to understand the basis of this myopathy as it will provide insight in the redox environment of the ER, the metabolic fluxes controlling ER status, having wider implications for further understanding the integration of muscle glucose and glucocorticoid homeostasis.
The G6P transporter (G6PT) and glucose homeostasis
G6PT deficiency results in glycogen storage disease 1b, which is manifest by poor glucose homeostasis and hepatic dysfunction. It is unknown how muscle is affected. We hypothesis that G6PT deficiency specifically in muscle will insulin sensitise it due to abrogation of GC interference and offer insight into ER cytosolic glucose metabolism, as the route for G6P flux in to the ER in muscle will be completely blocked. We are using G6PT muscle specific knockout so asses this hypothesis.
Tissue specific dissection of 11β-HSD1 function in obesity and insulin resistance
11β-HSD1 is an intracellular GC reactivating enzyme. Thus, independently of the HPA axis and delivery of adrenal derived GC, tissues can generate additional GC. In the fat of obese individuals 11β-HSD1 is often over expressed. Similarly, the site of most abundant activity is the liver and therefore its therapeutic inhibition could offer a way to alleviate the metabolic consequence of 11β-HSD1 over expression in obesity and type 2 diabetes, sensitising individuals towards insulin and ameliorating disease burden. We have generated liver, muscle and adipose tissue specific knockouts in mice to assess the exact contribution of 11β-HSD1 to local and systemic GC metabolism and metabolic homeostasis.
- Hexose-6-phosphate dehydrogenase (H6PDH) and the control of skeletal muscle glucose trafficking in metabolism
- The G6P transporter (G6PT) and glucose homeostasis
- Tissue specific dissection of 11β-HSD1 function in obesity and insulin resistance
- Soulier A, Blois SM, Sivakumaran S, Fallah-Arani F, Henderson S, Flutter B, Rabbitt EH, Stewart PM, Lavery GG, Bennett C, Curnow SJ and Chakraverty R (2013) Cell-intrinsic regulation of murine dendritic cell function and survival by pre-receptor amplification of glucocorticoid. Blood [Epub ahead of print]
- Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten EL, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW (2013) Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice. Endocrinology [Epub ahead of print]
- Tiganescu A, Tahrani AA, Morgan SA, Otranto M, Desmoulière A, Abrahams L, Hassan-Smith Z, Walker EA, Rabbitt EH, Cooper MS, Amrein K, Lavery GG and Stewart PM (2013) 11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest 123(7):3051-60
- Morgan SA, Gathercole LL, Simonet C, Hassan-Smith ZK, Bujalska I, Guest P, Abrahams L, Smith DM, Stewart PM, Lavery GG and Tomlinson JW (2013) Regulation of lipid metabolism by glucocorticoids and 11β-HSD1 in skeletal muscle. Endocrinology 154(7):2374-84
- Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW and Stewart PM (2013) 11β-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev 34(4):525-55
- Lavery GG, Idkowiak J, Sherlock M, Bujalska I, Ride JP, Saqib K, Hartmann MF, Hughes B, Wudy SA, De Schepper J, Arlt W, Krone N, Shackleton CH, Walker EA and Stewart PM (2013) Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling. Eur J Endocrinol 168(2):K19-26
- Abrahams L, Semjonous NM, Guest P, Zielinska A, Hughes B, Lavery GG and Stewart PM (2012) Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11β-HSD1 and H6PDH. J Endocrinol 214(3):367-72
Dr Gareth Lavery - School of Clinical and Experimental Medicine
Agnieszka Zielinska (BBSRC)
Craig Doig (BBSRC)
Emma McCabe (MRC)
Rowan Hardy (ARC)