Benefits and challenges to therapeutic targeting of bile acid circulation in cholestatic liver disease

Progress in our understanding of the molecular basis of bile acid (BA) transport in the liver, bile ducts, intestine and kidney have not only advanced our understanding of the pathophysiology of cholestasis and metabolic dysfunction-associated liver disease but also led to novel therapeutic approaches targeting BA transport and signaling within the entero-nephro-hepatic circulation. This includes BA transport modulators such as inhibitors of the apical BA-transport system in the terminal ileum and proximal renal tubule (IBAT/ASBT inhibitors) and basolateral (sinusoidal) BA uptake in hepatocytes (NTCP inhibitors). In addition to altering membrane transporter function by targeting IBAT/ASBT and NTCP, there are an array of potentially additive therapeutic approaches which include receptor agonists acting via nuclear receptor (FXR, PPAR)-mediated transcriptional modification of BA synthesis and transport genes and BA analogs such as norucholic acid (previously known as norUDCA) that undergo cholehepatic shunting. This article reviews established and emerging molecular and clinical rationales for therapeutic targeting of BA circulation and signaling in liver diseases with a specific focus on cholestatic disorders.