Molecular insight into the bile acid transporter NTCP

Bile acids have besides their emulsification function in the intestine also a signalling role in many metabolic pathways. Bile acids circulate in the body via the enterohepatic circulation. The bile acid transporter NTCP (sodium taurocholate cotransporting polypeptide) functions as the main bile acid uptake transporter in the liver. NTCP inhibition or deficiency results in elevated plasma bile acid concentrations. Additionally, NTCP is the entry receptor for the hepatitis B and delta virus. This thesis provides insights in NTCP function and viral infection influenced by molecular adaptions in NTCP and its interaction with other proteins. We identified that the two sugar residues on NTCP are essential for bile acid transport and HBV infection. Furthermore, competition between two signal-proteins which can bind to NTCP (Ubiquitin/SUMO) regulate the degradation of NTCP. We demonstrate that cholestasis‐induced accumulation of bile acids in the liver results in a FXR-independent increase in ER-stress which results in decreased calnexin expression leading to a reduction of NTCP protein expression and function. Besides, we identified calnexin and Stomatin as NTCP-interaction partners. The interaction between NTCP and Myrcludex B, a peptide which competes with HBV binding to NTCP and inhibits bile acid transporters was investigated by advanced microscopy. We show that NTCP bound- Myrcludex B can dissociate from NTCP and relocate on newly synthesized NTCP and thereby prolonging its presence on NTCP and thus its inhibitory effect on HBV infection. This mechanistical insight into NTCP regulation provides new possibilities to try and harness these processes for therapeutic use in virology and in metabolic disorders.