# Elucidating the Role of Organic Solute Transporter (OST) Alpha/Beta in Bile Acid Transport and Drug Interactions

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $14,090

## Abstract

Project Summary/Abstract
Organic solute transporter (OST) α/β, a heteromeric protein localized on the basolateral membrane of hepatic,
intestinal and kidney epithelial cells, is an important transporter involved in the homeostasis of bile acids (BAs)
and other steroid hormones. OSTα/β-deficient mice exhibit features of BA malabsorption. Hepatic expression of
OSTα/β is significantly increased in obstructive cholestasis and primary biliary cholangitis, suggesting that this
transporter provides an excretion pathway for BAs in cholestatic liver disease. OSTα/β is overexpressed in
patients with nonalcoholic steatohepatitis, and a link has been found between genetic defects in this transporter
and congenital diarrhea and cholestasis, implying a key role for OSTα/β in health and disease. Dysregulation of
BA disposition, particularly by drug-mediated inhibition of hepatic efflux transporters, can lead to hepatocellular
accumulation of lipophilic BAs resulting in hepatotoxicity. This is an important mechanism of drug-induced liver
injury (DILI), a major safety issue in drug development. However, very little is known about the role of OSTα/β in
BA-mediated DILI. A few BAs and drugs are known OSTα/β substrates and/or inhibitors, but a systematic study
of OSTα/β-mediated BA transport is lacking. Therefore, identifying which BAs are OSTα/β substrates, identifying
drugs that interact with OSTα/β-mediated BA transport, and elucidating OSTα/β residues that are crucial for BA
transport is vital to understanding the role of this transporter in human health, disease and DILI. Specific aims
will test the following hypotheses: 1) BA affinity for OSTα/β is a function of BA lipophilicity/hepatotoxicity; 2) drug-
induced alterations in OSTα/β-mediated BA transport are dependent on the BA species; and 3) evolutionarily
conserved, charged and hydrophilic/polar residues in the transmembrane domains of OSTα/β are crucial for
OSTα/β-mediated BA transport. Using a stable, OSTα/β-overexpressing human cell line and the clinically
relevant sandwich-cultured human hepatocyte model in the proposed project, the most prevalent hydrophilic and
lipophilic/hepatotoxic BAs will be analyzed to identify OSTα/β substrates and elucidate the interaction of drugs
with OSTα/β-mediated transport of these BA substrates. In Aim 1 of this project, OSTα/β-mediated transport
kinetics of specific BAs will be studied by overexpression or induction of OSTα/β. In Aim 2, drug-induced
alterations in OSTα/β-mediated BA disposition will be elucidated. To further reveal OSTα/β-mediated BA
transport mechanisms, critical amino acid residues in OSTα/β’s transmembrane domains will be investigated
(Aim 3). The results of the proposed studies will provide fundamental, and mechanistic information about the
role of OSTα/β in human health and disease, and the effect of DILI-associated drugs on OSTα/β-mediated BA
transport. These data will improve predictions of BA-mediated DILI using computational modeling. The resul...

## Key facts

- **NIH application ID:** 9868818
- **Project number:** 5F31DK120196-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** James John Beaudoin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $14,090
- **Award type:** 5
- **Project period:** 2019-02-15 → 2020-04-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868818

## Citation

> US National Institutes of Health, RePORTER application 9868818, Elucidating the Role of Organic Solute Transporter (OST) Alpha/Beta in Bile Acid Transport and Drug Interactions (5F31DK120196-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9868818. Licensed CC0.

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