Differential and organ-specific functions of organic solute transporter a and b in experimental cholestasis

Background & Aims: Organic solute transporter (OST) subunits OSTa and OSTb facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTa or OSTb display considerable variation in the level of bile acid malabsorption, chronic diarrhea, and signs of cholestasis. Herein, we generated and characterized a mouse model of OSTb deficiency.& nbsp;Methods: Ost beta(-/-)mice were generated using CRISR/Cas9 and compared to wild-type and Ost alpha(-/-)mice. OSTb was re-expressed in livers of Ost beta(-/-)mice using adeno-associated virus serotype 8 vectors. Cholestasis was induced in both models by bile duct ligation (BDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding.& nbsp;Results: Similar to Ost alpha(-/-)mice, Ost beta(-/-)mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ost beta(-/-)mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ost alpha(-/-)mice, induction of cholestasis in Ost beta(-/-)mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostb expression via adenoassociated virus-mediated overexpression did not rescue the phenotype of Ost beta(-/-)mice.& nbsp;Conclusions: OSTb is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Osta-/-mice, but it exerts distinct effects on survival and the liver phenotype, independent of its expression in the liver. Our findings provide insights into the variable clinical presentation of patients with OSTa and OSTb deficiencies.& nbsp;Lay summary: Organic solute transporter (OST) subunits OSTa and OSTb together facilitate the efflux of conjugated bile acids into the portal circulation. Osta knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostb knockout mice for the first time. Ost alpha and Ost beta knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostb knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTb, possibly as an interacting partner of other intestinal proteins. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Automated summary

This study highlights the pivotal role of OSTb in bile acid transport in the ileum. Knockout of Ostb showed a worsened phenotype in cholestasis compared to Ost alpha(-/-) mice, suggesting a distinct role of OSTb in influencing survival and liver phenotype.