Abstract
Background & AimsOrganic 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.MethodsOstβ-/- 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.ResultsSimilar 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.ConclusionsOSTβ 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 summaryOrganic 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.
Highlights
Bile acids facilitate the intestinal digestion and absorption of fats and fat-soluble vitamins
Increased expression levels of ileal Fgf[15], and decreased Asbt expression in Ostb-/- mice indicate the accumulation of bile acids in the enterocyte
OSTb is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to
Summary
Bile acids facilitate the intestinal digestion and absorption of fats and fat-soluble vitamins. FGF15/19 is released by the enterocyte into the portal circulation and binds to the FGF receptor 4 (FGFR4)-b-Klotho complex on hepatocytes, which triggers several pathways including the suppression of the rate-limiting enzyme in bile acid synthesis, CYP7A.3. Activation of FXR protects against bile acid overload in both enterocytes and hepatocytes. This is achieved by inhibiting bile acid influx via downregulation of the apical sodium-dependent bile acid transporter (ASBT) and the hepatic uptake transporter sodium taurocholate cotransporting polypeptide and stimulating export of bile acids by upregulation of efflux transporters, such as the bile salt export pump and the organic solute transporter ab (OSTa-OSTb).[4]. Organic solute transporter (OST) subunits OSTa and OSTb facilitate bile acid efflux from the enterocyte into the portal circulation. We generated and characterized a mouse model of OSTb deficiency
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