by Mark Wheeler

In Greek mythology, Prometheus, a hero and thief of fire, was punished by Zeus for the theft. Chained to a rock, each day an eagle would swoop down and eat his liver; each night, his liver would regrow. Perhaps, says Wendong Huang, Ph.D., assistant professor in the Department of Gene Regulation and Drug Discovery at City of Hope, it shows that thousands of years ago, humans had already recognized the regenerative powers of the liver.

Now, in work conducted primarily at Baylor College of Medicine and at City of Hope, Huang, David Moore, Ph.D., professor of molecular and cellular biology at Baylor, Xiongfei Huang, Ph.D., a City of Hope visiting scientist, and colleagues report the finding of a key receptor of bile acids that stimulates liver regeneration. The work appears in the April 14 issue of the journal Science.

In a hepatectomy (liver surgery), as much as 70 percent of the liver can be lost, yet remarkably, it will regrow back to full capacity within a short period of time, said Huang. The explanation for this may lay in evolution, since the liver filters harmful substances from the blood and is critical for the body’s metabolism. Without the liver, said Huang, “we would die, so it must be able to regenerate, and regenerate quickly.”

Huang wanted to know what triggers liver re-growth, since understanding how this happens could help scientists seeking to treat liver diseases, including liver cancer. Since the liver is the organ for metabolism, he and his colleagues reasoned, the signals for liver regeneration could be of a metabolic nature. That led them to look at bile acids, which are made in the liver and cycle back and forth between the liver and the intestine to help the absorption of fat and vitamins. But in addition, bile acids are signaling molecules that provide the body with key information about the state of the liver.

Because high levels of bile acids are toxic, said Huang, their levels need to be tightly controlled and maintained in homeostasis, or balance. When a piece of the liver is removed in a hepatectomy, the remaining portion is still exposed to high amounts of bile acids. Huang discovered that the bile acids activate a specific receptor called FXR that not only regulates levels of bile acids, but also is the trigger that activates liver regeneration.

“This receptor serves two separate functions that are closely related,” he said. “The primary function is to regulate metabolism. But if stress is high (that is, more acids than the remaining liver can handle after hepatectomy), then the FXR receptor will stimulate liver growth to increase liver size and bring everything back into balance.”

Huang found that mice bred to lack FXR have difficulty regenerating liver tissue. But when he and his colleagues fed the animals a diet that contains bile acids, the liver regenerated faster. “If you increase bile acids in animals, cell growth is stimulated and the liver cells start to replicate,” said Huang. “So the bile acids could be the stimulants for liver growth.”

Huang believes this finding could have important implications. “Liver regeneration is a critical step during liver carcinogenesis, and, for liver transplantation, stimulating liver growth is essential for some severe liver diseases. Thus the mechanism of liver regeneration is important for liver cancer and other liver diseases.”

Besides Huang, Moore and Xiongfei Huang, other scientists who participated in the research include Ke Ma, Jun Zhang, Mohammed Qatanani, Jun Liu, James Cuvillier and Bingning Dong. Funding for this study came from the National Institutes of Health.