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A long-standing mystery in bile acid biology has been solved.
Bile acids are often introduced as digestion helpers, but they are also powerful chemical messengers that help coordinate metabolism throughout the body. To do their jobs, these cholesterol-derived molecules must be shuttled efficiently between the liver, the intestine, and the blood in a recycling loop called enterohepatic circulation.
Scientists have mapped many of the transport steps that keep this loop running. Still, one crucial leg of the journey has been surprisingly hard to pin down: the handoff that moves bile acids out of intestinal cells and into the bloodstream. Because this route was long assumed to exist yet resisted clear molecular explanation, one reviewer dubbed it the “Northwest Passage” of bile acid transport: a pathway long presumed to exist but elusive to map.
A new study now fills in that missing link. Researchers led by Eric H. Xu (Xu Huaqiang) at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, working with MA Xiong of Renji Hospital, used cryo-EM structure determination, molecular dynamics simulations, and electrophysiological analyses to reveal how the transporter Ostα/β handles bile acids and why it does not behave like the better-known carriers in textbooks. Their results were recently published in Nature.
Structural Insights from Cryo-EM
In liver cells, bile acids are transported using a well-characterized system. Sodium-coupled or facilitative transporters allow bile acids to enter hepatocytes at the sinusoidal membrane, while ATP-binding cassette (ABC) transporters export them at the canalicular membrane.
Scientists assumed that intestinal cells used a similar strategy. However, in 2004, researchers identified the heterodimeric organic solute transporter Ostα/β as the primary exporter of bile acids at the basolateral membrane of enterocytes. Even so, exactly how this transporter functioned at the molecular level remained unknown.
To answer this question, the team produced and purified the human Ostα/β complex in mammalian cells and determined its structure at resolutions of 2.6–3.1 Å using single-particle cryo-electron microscopy. They found that the complex forms a symmetric tetramer made up of two heterodimers. Each Ostα subunit adopts a distinct seven-transmembrane structure that is “augmented” by a single transmembrane helix from Ostβ. This unusual structural arrangement helps explain why Ostα/β does not fit into any previously recognized transporter family.
Closer examination of the structure revealed a lateral binding groove within the membrane where substrates attach. This groove is supported by a cysteine-rich loop that undergoes extensive palmitoylation. These lipid modifications create a hydrophobic environment suited to amphipathic molecules such as bile acids.
Additional structures captured with taurolithocholic acid and dehydroepiandrosterone sulfate showed that charged amino acids inside the groove interact with negatively charged groups on the substrates, providing a molecular explanation for how the transporter achieves specificity.
A Voltage-Dependent Transport Pathway
Moreover, the researchers identified a hydrophilic tunnel extending from the binding groove toward the extracellular side of the transporter. Molecular dynamics simulations and electrophysiological recordings showed that substrates moved through this pathway in a voltage-dependent manner, directly converting bile acid flux into an electrical signal by using the intrinsic charge of cholic acid. These results provided a direct, quantitative readout of bile acid transport by recording transporter-associated currents, thus linking structure to transport in real time and with polarity control.
Together, the data support a model in which Ostα/β functions as a facilitative carrier whose transport direction is set by the combined electrochemical gradient of its substrates. Ostα/β mediates bidirectional flux with directionality shaped by substrate concentration gradients, membrane potential, and electrostatic interactions within the binding pocket. As a result, membrane voltage is not a passive background variable but an active determinant that biases transport toward export- or import-favored modes under physiological conditions.
This study goes beyond bile acid biology to show that Ostα/β and the TMEM184 family of proteins are likely orphan transporters rather than receptors based on their structural similarity and thus may share transport mechanisms. These results open up new avenues for studying poorly characterized membrane proteins and understanding how lipid environments tune transporter function.
Reference: “Structures of Ostα/β reveal a unique fold and bile acid transport mechanism” by Xuemei Yang, Nana Cui, Tianyu Li, Xinheng He, Heng Zhang, Canrong Wu, Yang Li, Xiong Ma and H. Eric Xu, 28 January 2026, Nature.
DOI: 10.1038/s41586-025-10029-7
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