Dissecting the steroid metabolome in the pathogenesis and treatment of metabolic liver disease

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We are currently in the midst of a global epidemic of metabolic disease that includes obesity and type 2 diabetes. These conditions are frequently associated with fat deposition in the liver, so-called non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disease that extends from simple fat accumulation through to inflammation (non-alcoholic steatohepatitis, NASH) which can progress to fibrosis and scarring and eventually lead to cirrhosis of the liver which may require a liver transplant. In addition, it significantly increases your risk of developing primary liver cancer (hepatocellular cancer, HCC). Within 5 years, this will become the commonest cause of liver transplantation. The condition is also associated with an increased risk of heart attacks and strokes as well as problems directly related to the liver. There are currently no specific treatments that are licenced for the treatment of NAFLD and the gold-standard test to diagnose the stage and severity of the condition (liver biopsy) is associated with significant complications. As part of this proposal, we will measure natural steroid hormone metabolites in urine samples from patients with NAFLD (as identified on liver biopsy) as well as HCC to see if this can provide an alternative way to diagnose and stage the severity of the disease without the need for a liver biopsy. This approach will be compared against standard blood tests as well as scans including magnetic resonance imaging. The data that we have generated leading up to this proposal have suggested that we can very effectively diagnose the most extreme ends of the NAFLD spectrum and this has helped to identify one specific steroid metabolizing enzyme (AKR1D1) that we believe to be crucial in the progression and development of NAFLD. We have already generated a mouse model with deletion of AKR1D1 and the female mice do not put on weight with a high fat diet and are protected from diabetes. Within this proposal we will further characterize the metabolism of these animals looking at food consumption, energy expenditure as well as using different dietary regimens to replicate all the stages of NAFLD to see if they are protected from the development of NAFLD and HCC. Finally, we will also begin to develop drugs that are specific inhibitors of AKR1D1 to see if these may represent potential treatments for NAFLD and metabolic liver disease in the future.