|Researchers reveal cholesterol control mechanisms|
September 15, 2000
Cholesterol-munching mice are aiding researchers in revealing protein receptors responsible for controlling cholesterol. The findings bring researchers a step closer to developing new lipid-lowering drugs that could increase good cholesterol, excrete the bad and inhibit the absorption of dietary cholesterol, says David J. Mangelsdorf, a pharmacologist at Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center in Dallas, Texas.
Using an experimental drug that targets key cholesterol-governing receptors, researchers switched off cholesterol absorption in mice that consumed 10 to 100 times more cholesterol than normal. Mice typically absorb 50 to 80 percent of dietary cholesterol, Mangelsdorf says, but with the use of the experimental drug LG268, the mice did not absorb any cholesterol.
Humans, like most mammals, produce enough cholesterol for the body without a need for dietary supplementation. Although cholesterol is essential for life, it can be a killer when the concentration gets too high in the blood.
Scientists have long suspected that mammals have a sensor that controls the elimination and absorption of dietary cholesterol, but how to activate the sensor remained a mystery. Researchers have now identified three proteinsretinoid, faresnoid and liver X receptors, or RXR, FXR and LXRthat act as a sort of biological switch, according to findings published in a recent issue of Science. The receptors work in teams to rid the body of too much cholesterol and inhibit lipid absorption.
LG268, as it turns out, activates RXR, which in turn activates LXR and FXR. Already under consideration for clinical use for chemotherapy and diabetes, LG268 enhances FXR's ability to repress a gene crucial for bile acid synthesis in the liver and cholesterol absorption in the intestine. It also activates 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.
Researchers now have two specific targetsFXR and LXRfor creating greater precision in managing cholesterol levels, says Mangelsdorf. Statins, the current cholesterol-lowering drugs, were first introduced in 1980. They work by inhibiting the amount of cholesterol the body produces internally.
Mangelsdorf says the statins are effective but limited. They can only reduce the amount of cholesterol in the body by up to 40 percent, and only inhibit the amount of cholesterol the body produces. Statins have no effect on dietary cholesterol, and presently, diet is the only remedy.
LG268 is a start toward new drug therapies but not a cure. While LG268 prevented mice from absorbing cholesterol, the mice compensated by stepping up production of cholesterol. "In thinking about drug therapies, we need to think of co-drugs," says Mangelsdorf.
Mangelsdorf envisions someday applying a combination of drugs: statins to control cholesterol production and drugs like LG268 to control dietary lipids. "Using both kinds of drugs could actually produce a net loss of cholesterol in the body," he says.
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