September 01, 2000
New Drugs Could Be More Effective at Lowering Cholesterol
Researchers have discovered two targets for a new generation of
cholesterol-lowering drugs that should allow greater precision in
managing cholesterol levels.
Howard Hughes Medical Institute (HHMI) investigator David J.
Mangelsdorf and colleague Joyce J. Repa, an HHMI associate at the
University of Texas Southwestern Medical Center, have switched off
cholesterol uptake in mice using a drug that targets key
cholesterol-governing receptors. Their experiments also reveal how the
receptors, LXR and FXR, control genes that regulate the body’s
cholesterol balance. Scientists from Tularik Inc., in South San
Francisco and Ligand Pharmaceuticals in San Diego also collaborated on
the research, which was published in the September 1, 2000, issue of
the journal Science.
“We were on a triple treasure hunt— to find possible ligands for these orphan receptors, to find their target genes and to characterize their biological roles.”
David J. Mangelsdorf
"Before this work, there were only hints that a protein-mediated
mechanism for cholesterol uptake existed," said Mangelsdorf. "We
believed that the process was not just a passive absorption through the
cell membrane, but we needed proof to support this idea. Although the
results from these studies in mice are promising, there's a long road
ahead before these compounds can be considered for human clinical
trials."
A key clue that cholesterol uptake is actively regulated emerged
from studies showing that mice can selectively avoid absorbing ingested
plant sterols, which have a chemical structure that is similar to
cholesterol. A second clue came from the observation that strains of
rats and mice differ in their ability to absorb cholesterol, suggesting
that there is a genetic component to control of cholesterol
metabolism.
Mangelsdorf said his team's current work began not as a search for
the mechanism of cholesterol uptake, but as an effort to identify the
hormone-like compounds—called ligands—that activate LXR and
FXR. These two orphan nuclear receptors are proteins that have the
ability to turn on genes in the nucleus, but their triggers remained
unknown, hence the term "orphan."
"We were on a triple treasure hunt—to find possible ligands
for these orphan receptors, to find their target genes and to
characterize their biological roles," said Mangelsdorf.
In previous work, the scientists had shown that LXR and FXR were
involved in disposing of excess cholesterol and in regulating bile
acids. When the group knocked out the LXR genes in mice, they found
that LXR controlled a key enzyme that produced bile acids from
cholesterol. Bile acids are generated to shed excess cholesterol and to
speed cholesterol absorption by making cholesterol more soluble.
"An important take-home lesson here is that because we could show
that these nuclear receptors had very direct and specific actions on
cholesterol balance, they are excellent targets for drugs to affect
cholesterol levels," said Mangelsdorf. "Like many other such nuclear
receptors, they are affected by drugs that can be taken orally and go
right to the receptors."
The group's next step was to see whether turning on LXR or FXR could
affect cholesterol uptake. While the scientists didn’t initially
have a drug that turned on either LXR or FXR, they did know that the
compound LG268 activates RXR, a protein that is required for both LXR
and FXR activity. RXR latches on to both LXR and FXR, and helps them
activate their target genes.
"Drugs like LG268 are especially promising because they are already
being considered for clinical use for chemotherapy and diabetes," said
Mangelsdorf. "But there had been no reason to test the drug’s
effect on cholesterol metabolism because nobody knew about LXR and FXR.
The development of drugs that specifically activate LXR or FXR may
prove even more beneficial."
When Mangelsdorf and his colleagues treated mice with LG268, they
found that the drug completely blocked the animals’ absorption of
cholesterol. "This was an astounding and dramatic effect," said
Mangelsdorf. "And it prompted us to try to understand both how the drug
inhibited cholesterol absorption in the intestine and promoted
excretion of excess cholesterol."
In extensive biochemical and genetic experiments on mice, the
scientists showed that LG268 enhances FXR’s ability to repress a
gene crucial for bile acid synthesis, thus reducing cholesterol
absorption by interfering with its solubility. They also found that
LG268 activated LXR’s ability to speed up production of ABC1, a
reverse cholesterol transporter that moves excess cholesterol out of
cells to the liver for excretion.
"We have discovered a potential therapeutic mechanism for regulating
cholesterol absorption from the diet and resorption of circulating
cholesterol. Also, we have identified a mechanism of cholesterol
transport in the intestine and the potential regulated transporter,"
said Mangelsdorf.
Although LG268 does induce fatty acid synthesis—an unwanted
side effect—Mangelsdorf believes that it may provide an excellent
foundation for the rational design of LG268-like compounds that do not
have side effects. This new generation of drugs to prevent cholesterol
absorption could work in concert with current cholesterol-lowering
drugs that inhibit internal cholesterol synthesis by the body. Such
cholesterol-synthesis-inhibiting drugs, called statins, achieve a
significant cholesterol-lowering effect, but they do not work for
everyonesince the body continues to absorb cholesterol from the
diet.
"Using both kinds of drugs could actually produce a net loss of
cholesterol in the body," said Mangelsdorf. "By carefully monitoring
drug dosages and cholesterol levels, you could essentially
‘dial-in’ exactly the level you wanted a person’s
cholesterol level to be."
In future work, the scientists will aim to improve their
understanding of the LXR- and FXR-regulatory machinery. They will also
concentrate on figuring out how ABC1 works. In transporting cholesterol
out of cells, ABC1 also eliminates cholesterol from immune cells called
macrophages. These cells are the culprits that form artery-clogging
fatty atherosclerotic plaques that can trigger heart attacks. Thus,
using drugs to activate ABC1 may prevent plaque buildup, said
Mangelsdorf.
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