Glow-in-the-dark zebrafish helping Jefferson scientists uncover cholesterol genes

Got zebrafish?

Biochemists at Jefferson Medical College are using zebrafish that glow to identify potential cholesterol-processing genes. In fact, they have found a gene they've dubbed "Fat Free" that plays a role in controlling cholesterol metabolism.

Steven Farber, Ph.D., assistant professor of microbiology and immunology at Jefferson Medical College and the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia and his co-workers there and at the University of Pennsylvania and the Carnegie Institution of Washington, have designed special fat molecules called "optical reporters" that glow when they are cut up by an enzyme in the intestine, enabling them to watch, biochemically speaking, digestion in transparent zebrafish embryos.

The embryos are helping the scientists find genes that regulate lipid processing. By identifying the genes behind lipid metabolism, scientists are hoping to establish the basis for new and improved cholesterol-controlling drugs.

Dr. Farber and his colleagues report their work May 18 in the journal Science.

The strategy is simple: create random genetic mutations in zebrafish by exposing males to a chemical agent, then breed families harboring the resulting mutations. Each family has a unique set of mutations. The researchers then mate brothers and sisters of those families to each other. They then feed the fluorescent molecule to resulting zebrafish embryos carrying various mutations and watch it light up in the digestive tract, liver and eventually the gallbladder, examining the pattern of fluorescence. The scientists subsequently screen for alterations in lipid processing.

"A number of genes that regulate lipid metabolism have yet to be determined," he says. "The beauty of the zebrafish genetic system is that it is an unbiased screen. We make random mutations and ask whether they interfere with lipid processing. "We believe that we are the first to use a biochemically based genetic sc

Contact: Steve Benowitz
Thomas Jefferson University

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