Intestinal transport and signaling of bile salts A focus on OSTα-OSTβ

The organic solute transporter alpha-beta (OSTα-OSTβ) facilitates bile acid efflux mainly in ileal enterocytes, liver and kidney, and protects cells from an overload of bile acids. Transcriptional upregulation of OSTα-OSTβ upon farnesoid X receptor (FXR) activation by bile acids is one of the key steps in this protective mechanism. The goal of this thesis was to gain a better understanding about the influence of OSTα-OSTβ on intestinal FXR, to unravel the regulation of the two different subunits that form this transporter and to gain more insight into the differences between OSTα and OSTβ in both mice and humans. We used a FRET-bile acid sensor to identify inhibitors of OSTα-OSTβ mediated bile acid efflux. Clofazimine was discovered as a novel inhibitor for OSTα-OSTβ and OSTα-OSTβ was validated as a target to enhance intestinal FXR activation. The same screen was used to identify 15 FDA-approved compounds that are currently used in clinical practice that were able to activate the FRET bile acid sensor. Furthermore, a kinase inhibitor screen was performed to identify kinases that modulate bile acid transport by OSTα-OSTβ. PI3Kγ was found to induce OSTα-OSTβ mediated bile acid efflux and may play a role in the protection against bile acid overload in cells. We also generated OSTβ knockout mice and provided their initial phenotyping and we investigated whether OSTβ deficiency in mice, like OSTα deficiency, is protective during cholestasis. The results of this thesis provide the first evidence that the OSTβ subunit might have an individual function.