Gene May Hold Key To Treating Life-Threatening Cholesterol

May 28, 1998

DALLAS, Texas, May 29, 1998 -- Findings from a study, in which a gene that speeds cholesterol metabolism was turned off, will help scientists develop better drugs for controlling life-threatening levels of the substance, researchers at UT Southwestern Medical Center at Dallas reported in the May 29 issue of Cell.

The gene that was turned off expresses liver X receptor, or LXR-alpha, a protein molecule found primarily in the nucleus of liver cells. The researchers engineered mice that lacked LXR-alpha, then fed them diets high in cholesterol. Without the receptor, the cholesterol levels in the mice rose so high it destroyed liver function. In humans, excessive amounts of cholesterol cause arteriosclerosis leading to heart attacks.

"Without LXR-alpha the animals completely lose their ability to deal with dietary cholesterol," said Dr. David Mangelsdorf, senior author of the paper, associate professor of pharmacology and Howard Hughes Medical Institute (HHMI) investigator. "We believe that this may work the same way in humans because the receptor is almost identical to the one in mice."

In normal animals, a hormone associated with cholesterol tells LXR-alpha to signal enzymes to increase the rate of cholesterol conversion to bile acid. Without LXR-alpha, this process doesn't occur, and cholesterol accumulates in the liver.

Mangelsdorf said scientists have found a perfect drug target in LXR-alpha. He plans to look for ways to biochemically design hormonal ligands that can speed metabolism and reduce dietary cholesterol levels in humans. Screening for mutations in LXR-alpha also may help identify inherited defects in cholesterol metabolism.

"This study suggests that we can develop an excellent drug to treat high levels of dietary cholesterol by altering the molecules that bind with LXR-alpha. Now we will use different levels of dietary cholesterol in longer-term studies to see if it causes atherogenesis in these genetically engineered mice," he said. "A key question is whether bile-acid synthesis is increased in humans through the same biochemical pathway as it is in mice."

The other researchers involved in the study were: Dr. Daniel Peet, HHMI associate; Dr. Stephen Turley, professor of internal medicine; Wenzhen Ma, HHMI research technician; Bethany Janowski, student research assistant in pharmacology; Dr. Jean-Marc Lobaccaro, HHMI associate; and Dr. Robert Hammer, associate professor of biochemistry and HHMI senior associate.

The Robert A. Welch Foundation, the Moss Heart Fund and the U.S. Public Health Service funded the study.
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UT Southwestern Medical Center

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