Scientists have discovered that bile acids, typically known for aiding digestion, also function as potent chemical messengers that help coordinate metabolic processes throughout the body. To perform these functions, these cholesterol-derived molecules must be efficiently transported between the liver, intestines, and bloodstream in a recycling loop known as the enterohepatic circulation.
A recent study from the Shanghai Institute for Biological Sciences, under the Chinese Academy of Sciences, details how researchers led by Eric Shu Huaqiang have mapped several steps involved in maintaining this crucial cycle.
However, one critical stage in this journey—the transport of bile acids from intestinal cells into the bloodstream—has remained surprisingly elusive.
Because this pathway had long been hypothesized but lacked a clear molecular explanation, one researcher dubbed it the “Northwest Passage” for bile acid transport, a route long suspected but difficult to pinpoint.
The new study now provides this missing link. Researchers, led by Eric, in collaboration with Ma Xiong from Renji Hospital, utilized cryo-electron microscopy, molecular dynamics simulations, and electrophysiological analyses to reveal how the Ostα/β transporter handles bile acids and why it doesn’t behave like the transporters described in standard textbooks. Their findings were recently published in the journal Nature.
The study noted that liver cells transport bile acids through a well-understood system, where sodium-dependent or facilitative transporters allow bile acids to enter liver cells across the sinusoidal membrane, even as ABC cassette transporters export them across the canalicular membrane.
Scientists had assumed that intestinal cells used a similar strategy. However, in 2004, researchers identified the organic solute transporter α/β (Ostα/β) as the primary source for bile acid transport across the basolateral membrane of intestinal cells. Despite this discovery, the transporter’s mechanism of action at the molecular level remained unknown.
Researchers found that the complex forms a symmetrical tetramer composed of two dissimilar subunits. Each Ostα subunit adopts a distinct seven-transmembrane helix structure, reinforced by a transmembrane helix from Ostβ. This unusual structural arrangement helps explain why Ostα/β doesn’t belong to any previously known transporter family.
Understanding how bile acids are transported is crucial, as disruptions in this process can lead to metabolic disorders and digestive issues. The findings from this research could potentially inform the development of new therapies targeting bile acid metabolism and related diseases.
