Hepatology and metabolism

Non-alcoholic fatty liver disease (NAFLD), considered the hepatic manifestation of metabolic syndrome, is the most common form of liver disease. It can progress from a fatty liver to nonalcoholic steatohepatitis (NASH), which is characterized with inflammation and fibrosis. Several pathways have been proposed to contribute to NAFLD progression, and a common link of these pathways appears to be bile acids. Other than facilitating absorption of lipids, bile acids are important signaling molecules that play a regulatory role in glucose, lipid and energy metabolism. Several bile acid signaling effects are mediated via activation of bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). In addition, bile acid signaling is also altered by hepatic bile acid uptake. The sodium taurocholate co-transporting polypeptide (NTCP) is the main uptake transporter of conjugated bile acids from the portal blood into the liver. Blocking NTCP can direct bile acid away from the liver and into the peripheral circulation, thereby prolonging signaling effects of endogenous bile acids. Inhibition of bile acid uptake can be beneficial since accumulation of hepatic bile acid can be toxic and cause inflammation, fibrosis and damage to the liver. Furthermore, prolonged bile acid signaling by genetic deletion of NTCP has shown to reduce body weight, hepatic steatosis and plasma cholesterol in mice with a high fat diet. NTCP deficiency has also not shown to be associated with negative health implications in both mice and human. Therefore, in this particular PhD project, we aim to explore possible beneficial effects of inhibiting NTCP-mediated bile uptake and prolonging bile acid signaling in order to manage metabolic and inflammatory syndrome, specifically, NAFLD/ NASH.