New research in animals suggests why the commonly prescribed cholesterol-lowering drug ezetimibe (Zetia) is so potent. The research, reported by scientists at Wake Forest University School of Medicine, is reported online today by the Journal of Clinical Investigation and will appear in the July 2 print issue.

It had previously been thought that the drug works by preventing cells in the intestine from absorbing cholesterol. The new research suggests that Zetia also works in the liver. In both locations, the drugs target is a protein known as NPC1L1 that moves cholesterol into the bodys cells. Zetia blocks the proteins actions so cholesterol cannot be absorbed.

Cholesterol comes not only from the foods we eat, but is also produced by the liver. The organ is involved in making cholesterol, as well as in taking up cholesterol and packaging it for the bodys use.

We know that this protein that the drug targets is expressed not only in the intestine, but is abundant in the human liver, said Ryan E. Temel, Ph.D., lead author. The scientists made the discovery about Zetias dual action by studying mice that were specially engineered to produce NPC1L1 in the liver.

When there were high levels of the protein in the liver, which enhanced cholesterol absorption by the cells, there was a drastic reduction in cholesterol levels in the bile. But when the mice were treated with Zetia, the cholesterol levels returned to normal, suggesting that the drug targets NPC1L1 in the liver.

These findings suggest that in humans, the drug may reduce cholesterol levels in the blood by inhibiting NPC1L1 function in both the intestine and liver, said Liqing Yu, M.D., Ph.D., senior researcher and an assistant professor of pathology, Section on Lipid Sciences.

The researchers theorize that when Zetia blocks this process in the liver, the cholesterol that cannot be absorbed is secreted into bile, the digestive juices
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