November 21, 2004
Promising New Directions for Gallstone Treatment
Polarizing light microscopy of gallbladder bile shows the deposition of cholesterol crystals, which can form gallstones under the right biochemical conditions.
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.
“What we saw was remarkable. 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.”
David J. Mangelsdorf
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 controls genes whose
proteins regulate the transport of bile acids and phospholipids from
the liver into the gallbladder. Previous studies had indicated that
FXR's activity is low in strains of mice that are more susceptible to
gallstone disease.
To study FXR's function, the researchers used a knockout mouse that
lacked the FXR gene. They then fed the mice a
“lithogenic” diet, which is designed to induce gallstone
formation because it is high in cholesterol and other components of
bile.
Mice are good models for CGD, said Mangelsdorf, because mice and
humans have the same genetic regulatory pathways to control the
components of bile. Also, the mouse version of CGD physiologically
mimics the disease that is observed in humans.
The researchers' analyses of bile components in the knockout mice
revealed cholesterol saturation and lower levels of biliary lipids,
resulting in cholesterol crystals — conditions that closely matched
those seen in humans with CGD. They also found that the bile acids
created the same hydrophobic conditions and inflammation that are
hallmarks of the human disease.
Finally, the researchers measured the activity of genes known to be
regulated by FXR in the knockout mice. Among these, they found low
activity in those involved in the transportation of lipid components of
bile.
“Once we had established that the FXR-deficient animals were
much more susceptible than normal animals to getting all the sequelae
of CGD, we decided to explore the effects of enhancing FXR activity in
a strain of mouse that was known to have FXR, but which was also
susceptible to the disease,” said Mangelsdorf. “We wanted
to determine whether such a drug could reestablish the proper
equilibrium of the bile components.”
To do this, the researchers gave CGD-susceptible mice, which were
fed a lithogenic diet, a synthetic compound — code-named GW4064 —
known to mimic the natural chemical that switches on FXR.
Mangelsdorf said the compound's effects were dramatic. “Their
cholesterol saturation, bile lipids, and bile hydrophobicity were
normal. And they showed no cholesterol crystal precipitation or
inflammation,” he said. In contrast, susceptible mice that did
not receive GW4064 showed evidence of gallstone formation. Mangelsdorf
said the studies also showed that FXR-knockout mice - in which the drug
was not expected to work - developed CGD more rapidly than the
susceptible mice.
“While we have not shown in this study that the drug that
activates FXR cures the disease once it starts, it does prevent
gallstones from occurring,” said Mangelsdorf. Although further
studies will be needed to determine whether the FXR-activating drug
could dissolve gallstones, their findings have clinical implications
for both diagnosis and prevention of CGD, he said.
“Humans are known to have a genetic component to risk of CGD
that has never been identified,” he said. “While surgical
removal of the gallbladder will remain the major treatment for existing
CGD, if we can identify those at genetic risk, we might be able to
prevent the disease. The lack of FXR might well be a diagnostic marker
for genetic predisposition to CGD.”
Also promising, said Mangelsdorf, is the potential for such a drug
to prevent pancreatic inflammation and “microlithiasis” in
people who have had their gallbladders removed because of gallstones.
In this disorder, a sludge of cholesterol-supersaturated bile inflames
the bile duct because of its abnormal properties. By restoring the
normal properties of bile, the drug would render it less viscous and
inflammatory.
While the drug used in the experiments is an expensive experimental
compound, said Mangelsdorf, “I have no doubt that the
pharmaceutical industry will use these findings as a basis for
commercial drug development, provided there are no serious side-effects
in humans.”
Image: Courtesy of David Mangelsdorf/HHMI at UT Southwestern Medical Center
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