Jefferson scientists unlocking secrets of cholesterol transport in body

February 23, 2004

Scientists at Jefferson Medical College and Jefferson's Kimmel Cancer Center have discovered one part of the mechanism behind a popular anti-cholesterol drug.

Steven Farber, Ph.D., assistant professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, Eric Smart, Ph.D., at the University of Kentucky and their co-workers have found that treating hypercholesterolemic mice with the drug ezetimibe (Zetia) disrupts a complex of two proteins in the intestine. At the same time, they used "antisense" molecules to prevent the formation of the complex in zebrafish, resulting in impaired cholesterol absorption in the intestine. The results suggest that these proteins are integral parts of an unidentified cholesterol transport system in the intestine.

A better understanding of the mechanisms behind cholesterol transport and absorption in the intestine could lead to improved therapies for obesity, diabetes and cardiovascular disease.

Dr. Farber and his colleagues report their findings February 23, 2004 in the Proceedings of the National Academy of Sciences. Specifically, the researchers found that two proteins - Caveolin 1 and Annexin 2 - were bound extremely tightly in the intestines. When this association was disrupted in zebrafish embryos, they absorbed a cholesterol "analog" more poorly. The scientists also found a similar close association of these proteins in mouse intestinal cells not found in other cells.

When the team treated mice that were fed a high fat Western diet with Zetia, the two proteins separated. "This was truly an unexpected result," Dr. Farber says. "How cholesterol levels can influence the ability of Zetia to disrupt the complex remains a mystery," he says, adding that both he and Dr. Smart plan to study the question in the near future. Ezetimibe blocks cholesterol absorption in the intestines, and as a result, scientists have inferred the existence of a cholesterol transport system in the intestines. The drug works differently than the popular statins, which inhibit cholesterol synthesis in the liver. But no one has identified molecularly how ezetimibe works.

"We've identified the components of the intestine that likely mediate the effect of Zetia," Dr. Farber says. "These proteins probably act as a shuttling system that moves cholesterol through cells." But, he adds, multiple proteins could be involved.

In a recent paper just published in the journal Science, researchers at Schering-Plough Research Institute demonstrated that mice that lack a protein, NPC1L1, absorb very little cholesterol, though the scientists failed to show a direct interaction between Zetia and NPC1L1. Dr. Farber's group was able to show that Calveolin 1 directly binds to Zetia. "This is a very exciting week in the lipid biology field," he says. "It's possible that NPC1L1 and our protein complex work together in some yet to be discovered manner."

Given the findings of the two papers, he says, "Now you could try different drugs to see which ones break up the complex, and perhaps not only make better drugs, but improve our understanding of the genes that regulate this process."
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