Active Enterohepatic Cycling is Not Required for the Choleretic Actions of 24-norUrsodeoxycholic Acid in Mice

The superior ability of nor ursodeoxycholic acid ( nor UDCA) to induce a bicarbonate-rich hypercholeresis has been attributed to its ability to undergo cholehepatic shunting and nor UDCA is currently being evaluated as a therapeutic for forms of liver disease. The goal of this study was to use mouse models to investigate contributions of bile acid transporters to the choleretic actions of nor UDCA. Here, we show that the apical sodium-dependent bile acid transporter (ASBT) and Organic solute transporter-alpha (OSTα) are dispensable for nor UDCA-stimulation of bile flow and biliary bicarbonate secretion in mice. Analysis of the liver transcriptome revealed that nor UDCA induced hepatic expression of a limited number of transporter genes, particularly organic anion transporting polypeptide 1a4 (Oatp1a4). However, nor UDCA potently stimulated a bicarbonate-rich hypercholeresis in Oatp1a/1b-deficient mice. Blocking intestinal bile acid reabsorption by co-administration of an ASBT inhibitor or bile acid sequestrant did not impact the ability of nor UDCA to induce bile flow in wildtype mice. The results support the concept that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of nor UDCA. Additionally, the findings support further investigation of the therapeutic synergy between nor UDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.