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Animal Research Uncovers Another Mechanism of Cholesterol Lowering Drug

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 that are stored in the gallbladder. Normally, most of biliary cholesterol is secreted from the body in the feces. However, when the bile contains too much cholesterol, gallstones can result. These hardened pieces of cholesterol can block the passageway from the gallbladder to the intestine, resulting in severe abdominal pain, liver damage and nutrient malabsorption.

The fact that Zetia works in two locations is positive because it makes it more effective as a cholesterol-lowering drug, said Temel. But our research suggests the potential for having too much cholesterol in the bile, which could possibly cause gallstones.

The researchers hope to study the question in monkeys and said more research is needed to see if the drug increases gallstone formation in some people. Until more research is done in animal models that naturally express the protein, it is difficult to say whether this would apply to humans, said Yu.


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