New Mechanism for Cholesterol Control

Because a surfeit of cholesterol contributes to heart attacks and cardiovascular diseases, millions of people try to lower their blood levels with drugs. These drugs stop the body from producing its own cholesterol, but they can't fight the cholesterol people eat. Now a mechanism has been found that helps the body rid itself of excess cholesterol, which opens up a new line of attack against this health risk.

The discovery is serendipitous, an offshoot of an attempt to assist the body's own approach to cholesterol. The body gets rid of excess cholesterol--as much as it can--by shipping it to the liver. There, a protein turns on genes that help bile acids break down the cholesterol. This protein seemed to offer a way to encourage the liver to work overtime. Indeed, in mice, levels of the protein are boosted by a drug called rexinoid. But when molecular pharmacologist David Mangelsdorf of the University of Texas Southwestern Medical Center in Dallas and colleagues tested the drug's effects on cholesterol, it didn't boost the breakdown in the liver. Instead, the drug seemed to prevent the absorption of cholesterol in the gut.

Mangelsdorf's team suspected that the drug enhanced the activity of a protein in the intestines. After a long search they found a protein, called ABC1, that pumps cholesterol back out of intestinal cells after it's been absorbed. Indeed, the researchers found that mice fed the drug produced more ABC1, they report in the 1 September issue of Science. But that wasn't all--the researchers uncovered two more unexpected powers. The drug caused immune cells called macrophages to eject their cholesterol, an important effect because cholesterol-laden macrophages help trigger artery-blocking plaques.

The research is "exciting because it suggests an entirely new mechanism for reducing cholesterol," says Steve Kliewer of Glaxo Wellcome Inc. in Research Triangle Park, North Carolina. But some rexinoids have dangerous side effects. For example, a rexinoid approved for treating certain types of late-stage cancer raises levels of lipids called triglycerides in the blood, which could worsen obesity and cardiovascular disease. And "side effects become a big issue" for otherwise healthy people who may take cholesterol-lowering drugs for decades, says Vincent Giguère, a molecular biologist at McGill University Health Centre in Montreal.

Related sites
David Mangelsdorf's lab
A fact sheet on cholesterol and heart disease

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