HMN 2026: How ‘Northwest Passage’ mechanism of bile acid transport reveals a voltage-dependent pathway

In a study published in Nature on January 28, a research team led by Eric H. Xu (Xu Huaqiang) from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, along with Ma Xiong from Renji Hospital, determined how Ost?/? transports bile acids and why it differs fundamentally from previously characterized carriers through cryo-EM structure determination, molecular dynamics simulations, and electrophysiological analyses.

Bile acids are essential for digestion, metabolism, and hormonal signaling. Their circulation between the liver and intestine, known as the enterohepatic circulation, depends on a coordinated network of membrane transporters. The export of bile acids from enterocytes into the bloodstream is one critical step, but the molecular mechanism is unknown, which is described as the “Northwest Passage” of bile acid transport by a reviewer.

Bile acid transport in hepatocytes requires that sodium-coupled or facilitative transporters mediate bile acid uptake at the sinusoidal membrane, while ATP-binding cassette (ABC) transporters drive bile acid export at the canalicular membrane. Such transport logic was assumed to exist in enterocytes and other bile acid-transporting epithelia. But in 2004, the identification of the heterodimeric organic solute transporter Ost?/? was identified as the major basolateral bile acid exporter.

Uncovering a unique transporter architecture

In this study, the researchers expressed and purified the human Ost?/? complex in mammalian cells, and solved its structure at 2.6–3.1 Å resolutions through single-particle cryo-electron microscopy. Ost?/? assembled as a symmetric tetramer composed of two heterodimers. Each Ost? subunit formed a unique seven-transmembrane fold, which was “augmented” by a single transmembrane helix of Ost?. This architecture explains why Ost?/? is not classified with the known transporter families.

Structural analysis revealed a lateral substrate-binding groove embedded within the membrane, which was stabilized by a cysteine-rich loop that underwent extensive palmitoylation. The lipid modifications created a hydrophobic environment that accommodated amphipathic substrates. Structures bound to taurolithocholic acid and dehydroepiandrosterone sulfate showed how charged residues within the groove interacted with negatively charged substrate groups, conferring specificity.

Voltage-dependent pathway for bile acids

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. Notably, they directly converted bile acid flux into an electrical signal by using the intrinsic charge of cholic acid, and provided a direct, quantitative readout of bile acid transport by recording transporter-associated currents, which links structure to transport in real time and with polarity control.

Together, the data support a model in which Ost?/? functions as a facilitative carrier whose transport direction is set by the combined electrochemical gradient of its substrates. Ost?/? mediates bidirectional flux with directionality shaped by substrate concentration gradients, membrane potential, and electrostatic interactions within the binding pocket. Thus, 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 shows that beyond bile acid biology, the structural similarity between Ost?/? and the TMEM184 family suggests that these proteins are likely orphan transporters rather than receptors, and may share related transport mechanisms, which opens up new avenues to study poorly characterized membrane proteins and to understand how lipid environments tune transporter function.

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