Recent advances in understanding and managing cholestasis

Abstract

Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, fibroblast growth factor 19, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.

Keywords: bile acid; cholestasis; hepatic; liver.

Figure 1.. Principle anticholestatic mechanism of fibroblast growth factor 19 (FGF19) analogues, apical sodium-dependent bile acid transporter (ASBT) inhibitors, and farnesoid X receptor (FXR) agonists.

Cholestasis results in the accumulation of bile acids in the enterohepatic bile acid circulation. Novel promising anticholestatic strategies aim to eliminate bile acids and reduce bile acid pool size predominately by either reducing de novo bile acid production or eliminating bile acids by interrupting enterohepatic bile acid circulation. Intrahepatic bile acid levels decrease. Left panel: FGF19 analogues mimic the action of endogenous FGF19, which is synthesized in the terminal ileum. FGF19 robustly represses hepatic de novo bile acid synthesis by blocking the rate-limiting enzyme of bile acid generation, cholesterol 7-alpha hydroxylase (CYP7A1). This reduces bile acid pool size and the amount of bile acids by suppression of the biliary loop of enterohepatic circulation. Middle panel: ASBT inhibitors selectively block bile acid re-uptake in the terminal ileum by blocking the bile acid transporter ASBT. Bile acids spill over into the colon and are lost via feces. This reduces bile acid pool size and the amount of bile acids by initially (1) suppression of the portal loop of enterohepatic circulation. Right panel: FXR agonists are not tissue specific but predominately activate FXR in the ileum and liver. FXR agonists suppress (-) bile acid synthesis via induction of FGF19-mediated CYP7A1 suppression from the ileum and via FXR- short heterodimer partner 1 (SHP)-mediated CYP7A1 repression from the liver. This reduces bile acid pool size. In addition, FXR agonists limit cellular bile acid accumulation by blocking ileal (via ASBT) and hepatic (via sodium taurocholate cotransporting polypeptide [NTCP]) bile acid uptake and by enforcing (+) ileal and hepatic (both via organic solute transporter α/β [OSTα/β]) bile acid export, leading to bile acid spill over into feces and systemic circulation.