Steroid metabolism

Steroid metabolism

The pandemic of obesity threatens to reverse the downward secular trends in cardiovascular disease because of its associations with hyperglycaemia, dyslipidaemia and hypertension (the Metabolic Syndrome). Research in Edinburgh has focused on steroid hormones as mediators of the metabolic complications of obesity and the progression to cardiovascular disease (Ann Int Med 2004, PNAS 2005). Since the formation of the Centre for Cardiovascular Science (CVS) in 1997, this has become a major focus, with Wellcome Trust and BHF Programme Grants and infrastructural awards (BHF Int Physiol, WTCRF) facilitating translation from rodents to humans.

11b-HSD1 structureCurrent studies of 11b-HSD1 are focused on mechanisms for tissue-specific regulation, including in the vessel wall (see theme Vascular Injury Inflammation and Repair – Glucocorticoids and Vascular Remodelling), and the interplay between intra-adipose steroid signalling and intra-adipose inflammation (macrophage infiltration; with Dr Hughes & Professor Sir John Savill, CIR) and vascular dysfunction. Cell-specific transgenic models are being expanded. A BAC transgenic approach with mutagenesis in the mouse promoter is underway to dissect tissue-specific regulation, to be supplemented by locus substitution with low and high-risk human haplotypes. Real time imaging of tissue steroid metabolism in vivo by MRS is being developed with Chemistry and Physics support. Fatty acid and lipoprotein tracer techniques are established to dissect effects on ectopic fat accumulation and steatohepatitis (with Professor Iredale, CIR).

To understand the role of other steroid metabolising enzymes in adipose tissue, susceptibility to obesity and cardiometabolic disease is being explored in aromatase (with E Simpson, Clayton, Australia) and 5a-reductase (Dr Andrew) knockout mice. These are readily translated to humans using available pharmacology and novel stable isotope tracers (Professor Walker, Dr Andrew). Given recent data suggesting dysregulation of steroid receptor expression in obesity, complementary studies in adipose-selective glucocorticoid (Professor Chapman) and androgen receptor (Dr McInnes with Professor Saunders, Centre for Reproductive Biology) knockout mice are underway.