The pronounced choleretic properties of
24-norUrsodeoxycholic acid (norUDCA) to induce
bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role of the
bile acid transporters. Here, we show that the
apical sodium-dependent bile acid transporter (ASBT), organic solute transporter-α (OSTα), and organic
anion transporting
polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA stimulation of bile flow and biliary
bicarbonate secretion.
Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. In mouse large cholangiocytes, norUDCA potently stimulated
chloride currents that were blocked by
siRNA silencing and pharmacological inhibition of
calcium-activated chloride channel transmembrane member 16A (TMEM16A) but unaffected by ASBT inhibition. In agreement, blocking intestinal
bile acid reabsorption by coadministration of an ASBT inhibitor or
bile acid sequestrant did not impact norUDCA stimulation of bile flow in WT mice. The results indicate that these major
bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or
bile acid sequestrants for cholestatic
liver disease.