Targeting hepatic bile salt uptake to treat obesity-related metabolic disorders

Over the recent years, bile acids are no longer only recognized as lipid solubilizing molecules in the intestine but also identified as complex signaling hormones contributing to the regulation of many metabolic pathways. In the liver, the sodium taurocholate co-transporting polypeptide (NTCP) functions as the main uptake transporter of conjugated bile acids and inhibition or deficiency of this transporter leads to (temporary) elevated bile acid levels. Additionally, NTCP is the entry receptor for the hepatitis B and delta virus. In the first part of this thesis, a screening platform was developed to identify novel NTCP inhibitors. Using this method, 5 hits were identified that inhibited NTCP-mediated bile acid transport as well as hepatitis B and delta infection in cell lines. Next, we studied the molecular interaction between NTCP and the NTCP inhibitor Myrcludex B. We show that NTCP-bound Myrcludex B dissociates and relocates to newly formed NTCP molecules and thereby prolonging its presence, and thus its inhibitory potential, on the plasma membrane. In the second part of this thesis, the metabolic consequences of temporary elevated bile acid levels were studied using NTCP knockout (KO) mice and the NTCP inhibitor Myrcludex B. On a high fat diet, NTCP KO mice or mice treated with Myrcludex B had a lower body weight and decreased fat content in the liver compared to control animals. Mechanistically, decreased intestinal fat absorption and increased energy expenditure by brown adipose tissue played an important role. Therefore, NTCP is an attractive target in the treatment of metabolic diseases.