Bile salt transport, metabolite signaling, liver diseases

Bile salts are important signaling molecules that regulate glucose, lipid, and energy metabolism. Many of their effects are mediated through activation of bile salt-responsive receptors. Importantly, the therapeutic potential of bile salts can be harnessed by inhibiting the hepatic bile salt transporter, the sodium taurocholate co-transporting polypeptide (NTCP). NTCP inhibition redirects bile salts from the liver into the systermic circulation, thereby prolonging systemic bile salt signaling. In this PhD project, the therapeutic effects of the NTCP inhibitor Bulevirtide were investigated in several liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), ulcerative colitis, and primary sclerosing cholangitis (PSC). To elucidate mechanisms, we screened over 300 G protein-coupled receptors (GPCRs), leading to identification of novel bile salt-responsive receptors that might regulate the beneficial effects of bile salt signling. Additionally, as NTCP serves as the entry receptor for Hepatitis B virus (HBV), post-translational modifications of NTCP, including ubiquitination, SUMOylation, and degradation, were examined to understand their role in regulating viral entry, providing a potential new strategy to combat HBV infection.