Modulating the enterohepatic circulation in cholestatic and metabolic liver diseases Therapeutic perspectives

Bile salts are synthesized in the liver and temporarily stored in the gall bladder, before they are released in the small intestine upon food intake. Here, they help with the digestion and absorption of food and nutrients. The enterohepatic circulation is the circulation of bile salts from the liver to the gall bladder, the small intestine and back to the liver via the portal vein. The enterohepatic circulation is fully dependent on the presence of multiple bile salt transporters. Sodium taurocholate cotransporting polypeptide (NTCP) is the main hepatic bile salt uptake transporter, while the apical sodium-dependent bile acid transporter (ASBT) is expressed in the small intestine and kidneys, where it prevents bile salts from being secreted in respectively feces and urine. During cholestasis, bile flow from the liver towards the small intestine is disturbed or completely blocked, causing severe liver damage when left untreated. Current treatment strategies are not always effective, and are associated with unwanted side-effects such as diarrhea. In this thesis, we explore new therapeutic strategies involving bile salt transport and signalling, to improve liver health in cholestatic liver diseases such as primary biliary cholangitis (PPC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome but also metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunctionassociated steatohepatitis (MASH).