Differential and organ-specific functions of organic solute transporter α and β in experimental cholestasis

Abstract

Background & aims: Organic solute transporter (OST) subunits OSTα and OSTβ facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTα or OSTβ 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 OSTβ deficiency.

Methods: Ostβ ^-/- mice were generated using CRISR/Cas9 and compared to wild-type and Ostα ^-/- mice. OSTβ was re-expressed in livers of Ostβ ^-/- 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.

Results: Similar to Ostα ^-/- mice, Ostβ ^-/- mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ostβ ^-/- mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ostα ^-/- mice, induction of cholestasis in Ostβ ^-/- mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostβ expression via adeno-associated virus-mediated overexpression did not rescue the phenotype of Ostβ ^-/- mice.

Conclusions: OSTβ is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Ostα ^-/- 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 OSTα and OSTβ deficiencies.

Lay summary: Organic solute transporter (OST) subunits OSTα and OSTβ together facilitate the efflux of conjugated bile acids into the portal circulation. Ostα knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostβ knockout mice for the first time. Ostα and Ostβ knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostβ knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTβ, possibly as an interacting partner of other intestinal proteins.

Keywords: AAV8, adeno-associated virus serotype 8; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ASBT; ASBT, apical sodium-dependent bile acid transporter; AST, aspartate aminotransferase; BDL, bile duct ligation; BSEP; CDX2, caudal type homeobox 2; Cholestasis; DDC, 3.5-diethoxycarbonyl-1.4-dihydrocollidine; FGF, fibroblast growth factor; FXR; FXR, farnesoid X receptor; NTCP; OST, organic solute transporter; SLC51A; bile acid; diarrhea.