Dr. Ming Zhou

Liver cells synthesize bile acids, which are then secreted via the biliary tract into the small intestine, where they help absorb fats and fat-soluble vitamins. In a natural form of recycling, the bile acids are then retrieved from the intestine and returned to the liver to begin the process of secretion again.

A key element of this circulation is a molecule known as the apical sodium-dependent bile acid transporter (ASBT). But how it did its work was unclear until researchers led by those at Baylor College of Medicine (www.bcm.edu) described the structure of the molecule, which contains a mobile unit or “elevator car” that transports the bile acids from one side of the molecule to the other, crossing the membrane in the process. A report on the work appears in the latest issue of the journal Nature.

To solve the structure of ASBT, Dr. Ming Zhou, associate professor of biochemistry and molecular biology at BCM, and his colleagues used special technology involving crystallography on a bacterial form (a homolog) of the ASBT.

Acts like elevator car

“This protein is very interesting,” said Zhou. “The fundamental problem we had to answer was that we had a large molecule (bile acid) with a negative charge that made it difficult to get through the membrane. What motion does the protein undergo to get it from one side of the bilayer to the other? The structures that we solved showed that a domain in the transporter protein is mobile, acting almost as an ‘elevator car’ that takes bile acid from one side of the transporter across the membrane to the other side.”

That finding has another significance, said Dr. Elena J. Levin, a first author of the report and a postdoctoral associate in Zhou’s laboratory. Pharmaceutical firms are pursuing this transporter as a drug target. If they can increase the production of bile acids, then the transporter could have significance as a cholesterol-fighting drug.

Even more intriguing is the fact that it could be used to take drugs into the liver, she said.

Delivery system?

“The protein can transport very big molecules,” she said. “It could be used to deliver drugs to the liver in a targeted way.

The transporters work in an interesting way, making use of sodium ions, said Zhou. In essence, ASBT works in a manner that is contradictory. When it takes the bile acid, it is transporting it from the lumen of the intestine with a low concentration to a higher concentration within the cells lining the intestine. The sodium ion provides the answer. Sodium is higher outside of cells than inside, and the transporter uses that fact to pull the bile acid “uphill,” said Zhou.

“The structure uncovered by the BCM team indicates how the two halves of the transporter work together to move bile acids from outside the cell membrane to inside the cell. Information about how the transporter recognizes and interacts with the large cargo may allow researchers to design and attach inhibitors and other therapeutic compounds to bile acids for specific uptake,” said Dr. Jean Chin of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research.

Others who took part in this work include Xiaoming Zhou, a co-first author, Yaping Pan and Jason G. McCoy, all of BCM; Ruchika Sharma of Columbia University in New York; Brian Kloss and Renato Bruni of the New York Consortium on Membrane Protein Structure; and Matthias Quick, co-corresponding author at the Department of Psychiatry at Columbia University and the New York State Psychiatric Institute. Xiaoming Zhou is now at Columbia University and Ruchika Sharma is now with the Irish Medicine Board.

Funding for this work came from the U.S. National Institutes of Health (R01DK088057, R01GM098878, U54GM095315, and U54GM087519), the American Heart Association (12EIA8850017) and the Cancer Prevention and Research Institute of Texas (R12MZ).