Bile acids, receptor key in regenerating livers

April 13, 2006

HOUSTON (April 14, 2006) - Bile must have been the most important thing in medicine for the physicians of ancient Greece and Rome. Yellow bile and black bile are half of the four humors that they believed made up the body, along with blood and phlegm. In their view, restoring health required correcting imbalances in these four components.

Studies by researchers from Baylor College of Medicine in a report that appears in today's issue of the journal Science suggest that they may have been on the right track.

In fact, regenerating liver tissue may depend on signals sent out when there is an imbalance in bile, said Dr. David Moore, BCM professor of molecular and cellular biology. He and colleagues at BCM identified an imbalance of bile, specifically bile acids, as a major signal for this process.

Liver is an unusual organ because it can regrow when injured.

Understanding how this happens could help physicians seeking to treat liver disease.

Bile acids are made in the liver and are the "detergents" of fat metabolism, said Moore. However, they are also signaling molecules that provide the body with key information about the state of the liver.

"They are released into the gut as part of digestion, reabsorbed and then back to the liver. More than 90 percent are cycled," he said. "You do not get rid of the bile acids when you lose a piece of liver," said Moore "Instead, you expose the remaining portion to a higher relative amount of bile acids, sending a signal through a specific receptor called FXR to activate liver regeneration."

Animals bred to lack FXR have difficulty regenerating liver, he said. And when he and his colleagues fed animals a diet that contains bile acids, the liver regenerated faster.

Those who receive drugs that sequester bile acids (such as drugs used to lower cholesterol) cannot regenerate liver.

Drugs could be developed to take advantage of this finding, promoting the growth of liver in some instances.

"People are interested in this," said Moore. "Can you promote the growth of liver cells to restore liver function? People are also interested in treating liver with disease with hepatocytes or liver cells."

The experiments carried out in his laboratory indicate that equilibrium in liver growth and function is maintained by FXR and possibly other receptors.

FXR and perhaps others as-yet unidentified receptors sense the ability of the liver to function. When it does not function well, one or more receptors are activated to protect the liver cells and enable the organ to grow. In this view, the liver grows until its function is restored and the signal for regeneration is lost.

In Greek legend, Prometheus, who gave man fire, was punished by Zeus. Each day, Zeus' eagle would eat his flesh and his liver. Overnight, the liver would regenerate and heal. With the dawn, the dreadful process began again.

In a way, said Moore, these studies are a scientific way to explain the regenerative process told in that legend.

Others who participated in the research include: Drs. Wendong Huang, Ke Ma, Jun Zhang, Mohammed Qatanani, James Cuvillier, Jun Liu, Bingning Dong and Xiongfei Huang. Dr. Wendong Huang and Dr. Xiongfei Huang are now at City of Hope in Duarte, California, and Dr. Jun Zhang is at Stanford University.
Funding for this study came from the National Institutes of Health.

Baylor College of Medicine

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