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Studies suggest promising new directions for gallstone treatment

A promising experimental compound prevents cholesterol gallstone disease in mice by stimulating the biochemical pathway that controls bile acid secretion by the liver, according to new studies by Howard Hughes Medical Institute researchers.

The findings suggest new approaches to developing drugs to prevent the disease, which afflicts some 20 million people a year. The studies also propose novel strategies for developing diagnostic tests to identify people with a genetically increased risk for developing gallstones.

A research team led by David J. Mangelsdorf, a Howard Hughes Medical Institute (HHMI) investigator at the University of Texas Southwestern Medical Center at Dallas, published its findings November 21, 2004, in the advance online version of the journal Nature Medicine. Co-authors of the paper included HHMI research associate Antonio Moschetta and Angie Bookout in Mangelsdorf's laboratory.

"What we saw was remarkable," said Mangelsdorf. "After just five to seven days of treatment, these animals, which were on a diet that would normally produce cholesterol gallstone disease, showed no trace of the disease."

Gallstones are formed by a disruption in the normal balance of bile acids and phospholipids that are pumped from the liver into the gall bladder. Bile then becomes supersaturated with cholesterol, which is still being pumped into the bile under control of another metabolic pathway. This supersaturation causes the cholesterol to precipitate as crystals, which, under conditions created by the chemical imbalance, can form gallstones. The subsequent change in biochemical conditions and gallstone formation then triggers inflammation, which is the major symptom of patients suffering from cholesterol gallstone disease (CGD).

In their studies, the researchers sought to determine the role of a protein known as farnesoid X receptor (FXR), which c
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
22-Nov-2004


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