Doctor of Philosophy

dissertationThe metabolic syndrome is a cluster of comorbidities including glucose intolerance, dyslipidemia, obesity and hypertension, with insulin resistance as a central pathogenic driver. The clinical significance of insulin resistance as a predictor of type 2 diabetes (T2DM) is being recognized. For individuals with T2DM, insulin resistance leading to an impaired ability to suppress hepatic gluconeogenesis is the main mechanism sustaining hepatic glucose production (HGP) after a meal. This aberrant HGP is the main cause of fasting hyperglycemia in T2DM. Hepatic steatosis - aberrant accumulation of neutral lipids in the liver - is an early feature of non-alcoholic fatty liver disease (NAFLD) present in greater than 70% of obese individuals. It is often considered the "liver equivalent of the metabolic syndrome", but studies indicate that it precedes and predicts insulin resistance and the metabolic syndrome. A percentage of individuals with steatosis will progress to steatohepatitis and ultimately fibrosis, cirrhosis and hepatocellular carcinoma (HCC), though this does not always occur linearly. HCC is currently the fastest growing cause of cancer-related death and this reflects the increase in NAFLD. These studies focused on two regulators of hepatic glucose and lipid metabolism - nuclear receptor small heterodimer partner (SHP) and retinol binding protein 4 (RBP4) receptor stimulated by retinoic acid 6-like (STRA6L). Firstly, we studied the role of SHP in novel aspects of liver function and metabolism. We performed RNA-sequencing on Shp-/- mice and compared these data to publically available transcriptomic analyses of human liver disease. This enabled us to identify putative SHP target genes that may regulate chronic liver disease. We also placed Shp-/- mice on the Leiber-DeCarli ethanol chronic and binge diet model of steatosis to identify how SHP regulates alcoholic steatosis. Secondly, we investigated the role of STRA6L in RBP4 action on the liver. We cultured hepatocytes of Stra6l-/- mice and treated these with RBP4 and also placed Stra6l-/- mice on a high-fat high-sucrose diet where RBP4 levels are increased. These studies allowed us to identify that STRA6L regulates the ability of RBP4 to induce insulin resistance and hepatic steatosis