ABSTRACT
The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 11/physiology , Bile Acids and Salts/metabolism , Hepatocytes/cytology , Hepatocytes/metabolism , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Biological Transport , CRISPR-Cas Systems , Cell Culture Techniques/methods , Cell Differentiation , Cells, Cultured , Gene Editing , Humans , Models, Biological , MutationABSTRACT
The main trigger for liver injury in acquired cholestatic liver disease remains unclear. However, the accumulation of bile acids (BAs) undoubtedly plays a role. Recent progress in deciphering the pathomechanisms of inborn cholestatic liver diseases, decoding mechanisms of BA-induced cell death, and generating modern BA-derived drugs has improved the understanding of the regulation of BA synthesis and transport. Now is the appropriate time to reassess current knowledge about the specific role of BAs in hepatobiliary injury.
