Glucocorticoid metabolism and the control of metabolic phenotype.
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
Obesity is associated with medical complications that include heart attacks, strokes, type 2 diabetes and the development of fatty liver disease which can progress to liver failure. The mechanisms that contribute to fat deposition within the liver are not fully understood and we believe that increased local production and / or decreased breakdown of the steroid hormone, cortisol, may contribute to the disease. In addition, cortisol acting on fat within the abdomen may fuel fatty liver disease by increasing delivery of fat precursors to the liver. Importantly, patients who either produce too much cortisol or who are prescribed large doses of steroid hormones develop many of these complications including obesity and fatty liver disease.
We will use cells cultured from liver and fat to determine the effect of cortisol on fat accumulation. We will also assess the impact of modifying production and break down of cortisol. We will create rodent models in which we have genetically manipulated the enzymes that produce and breakdown cortisol. We believe that decreasing cortisol production and enhancing breakdown will have beneficial effects. Finally, we will conduct clinical studies using drugs that decrease cortisol production to see if they can decrease fat accumulation within the liver.
We will use cells cultured from liver and fat to determine the effect of cortisol on fat accumulation. We will also assess the impact of modifying production and break down of cortisol. We will create rodent models in which we have genetically manipulated the enzymes that produce and breakdown cortisol. We believe that decreasing cortisol production and enhancing breakdown will have beneficial effects. Finally, we will conduct clinical studies using drugs that decrease cortisol production to see if they can decrease fat accumulation within the liver.
Technical Summary
The global epidemic of obesity has been estimated to cost the UK economy up to £16billion/yr (Foresight report), and translates to a decrease in life expectancy to the individual of approximately 10 years. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic and is a spectrum of disease that ranges from simple fat accumulation (hepatic steatosis), to non-alcoholic steatohepatitis, to fibrosis, cirrhosis and liver failure; within the next 5 years, NAFLD is likely to become the leading cause of liver failure word-wide. Patients with glucocorticoid (GC) excess, Cushing‘s syndrome, develop a phenotype characterized by intra-abdominal fat deposition and insulin resistance and NAFLD in 20% of cases. However, in the vast majority of cases of NAFLD, circulating GC levels are not elevated. In liver and adipose, GC availability to bind and activate the glucocorticoid receptor is controlled by a series of enzymes that either generate (11?-hydroxysteroid dehydrogenase type 1, 11?-HSD1) or inactivate GC (A-ring reductases). We hypothesize that increased GC availability to liver and intra-abdominal adipose tissue through increased 11?-HSD1 and / or decreased A-ring reductases, in the context of normal circulating GC levels, predisposes to the development of NAFLD and hepatic insulin resistance.
We will adopt a translational approach, combining in vitro experiments, rodent models and clinical studies to define in detail the impact of GCs and their pre-receptor metabolism, upon lipid homeostasis and insulin sensitivity in liver and intra-abdominal adipose tissue. Inhibition of 11 -HSD1 using shRNA and specific inhibitors in cell culture and rodent models will allow us to define the precise impact upon lipid metabolism and insulin sensitivity. These studies will be endorsed by the generation of a rodent model with targeted genetic deletion of 11 -HSD1 specifically within the liver. Clinical studies using selective 11 -HSD1 inhibitors will incorporate state-of-the-art investigative techniques including stable isotopes, microdialysis, tissue biopsies and magnetic resonance spectroscopy to determine the metabolic impact of 11 -HSD1 inhibition. We will explore the role of the A-ring reductases by modifying gene expression in vitro (transient transfection and generation of stable cell lines) and in rodent studies (hepatic transgenic over-expression and in vivo silencing using adenovirally delivered shRNA) and examining the metabolic impact of A-ring reductase inhibition in a clinical study.
Overall, these studies will determine the contribution of GC pre-receptor metabolism to the pathogenesis of NAFLD and insulin resistance, highlighting the role of both GC regeneration and clearance. They will generate novel translational research outcomes, providing mechanistic insight, as well as improvements in patient health.
We will adopt a translational approach, combining in vitro experiments, rodent models and clinical studies to define in detail the impact of GCs and their pre-receptor metabolism, upon lipid homeostasis and insulin sensitivity in liver and intra-abdominal adipose tissue. Inhibition of 11 -HSD1 using shRNA and specific inhibitors in cell culture and rodent models will allow us to define the precise impact upon lipid metabolism and insulin sensitivity. These studies will be endorsed by the generation of a rodent model with targeted genetic deletion of 11 -HSD1 specifically within the liver. Clinical studies using selective 11 -HSD1 inhibitors will incorporate state-of-the-art investigative techniques including stable isotopes, microdialysis, tissue biopsies and magnetic resonance spectroscopy to determine the metabolic impact of 11 -HSD1 inhibition. We will explore the role of the A-ring reductases by modifying gene expression in vitro (transient transfection and generation of stable cell lines) and in rodent studies (hepatic transgenic over-expression and in vivo silencing using adenovirally delivered shRNA) and examining the metabolic impact of A-ring reductase inhibition in a clinical study.
Overall, these studies will determine the contribution of GC pre-receptor metabolism to the pathogenesis of NAFLD and insulin resistance, highlighting the role of both GC regeneration and clearance. They will generate novel translational research outcomes, providing mechanistic insight, as well as improvements in patient health.
