<i>Abcb4</i> Haploinsufficiency Sensitises Mice to a Diet‐Induced <scp>PSC</scp> ‐Like Hepatobiliary Phenotype With Gallstone Formation

ABSTRACT ABCB4 translocates phospholipids (PL) into bile to buffer the toxicity of bile acids (BA) and free cholesterol (CHOL). While recessively inherited ABCB4 deficiency causes childhood Progressive Familial Intrahepatic Cholestasis type 3, haploinsufficiency has been linked to adult‐onset hepatobiliary diseases. To model this partial defect, we challenged phenotypically normal Abcb4 +/− mice, which have a toxic biliary BA/PL ratio, with diets supplemented with different lipids. Within 1 week, Abcb4 +/− mice fed a lithogenic diet rapidly developed severe phenotypes of cholestasis (elevated ALP and sTBA) and hepatic inflammation (increases in ALT and AST), as well as accelerated cholesterol calculi formation. By 6 weeks, animals on diet developed florid cholangitis (ductular reaction, immune cell infiltration, elevated cytokines) and peri‐portal fibrosis. This model demonstrates that a partial deficit in biliary PL secretion under conditions of environmental stress can act as a critical predisposing factor for adult‐onset hepatobiliary diseases like Primary Sclerosing Cholangitis. This model is suitable for evaluating therapeutics targeting abnormal bile composition.