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Jefferson scientists uncover lethal gene mutation key to blocking cholesterol processing

(PHILADELPHIA) When Jefferson Medical College researcher Shiu-Ying Ho, Ph.D., and her colleagues first created a mutation that limited the absorption of lipids and cholesterol into the bloodstream in zebrafish, the possibilities seemed endless. The discovery boded well for new insights into mechanisms behind lipid and cholesterol processing, and in turn, the potential development of new cholesterol-controlling drugs.

While Dr. Ho, assistant professor of biochemistry and molecular biology at Jefferson Medical College of Thomas Jefferson University and Jefferson's Kimmel Cancer Center in Philadelphia, and former Jefferson colleague Steven Farber, Ph.D., and Michael Pack, Ph.D., reported the findings in Science in 2001, one huge obstacle remained: identifying a gene behind the condition.

Now, Dr. Ho, Dr. Farber, now at the Carnegie Institution of Washington, and Dr. Pack at the University of Pennsylvania School of Medicine, have found a gene, which they dubbed fat free. Reporting in the April issue of the journal Cell Metabolism, the team explains that disrupting the gene interferes with the ability to absorb lipids through the intestine. These fish die when they are about a one and half weeks old because of this defect, even though they look normal and swallow properly.

The scientists found problems in mutant zebrafish bile duct and pancreatic cells that help with lipid digestion, in addition to defects in the cells that line the intestine, where fat and cholesterol absorption take place. Specifically, they found abnormalities in the Golgi apparatus, which holds newly made or recycled proteins that help with fat metabolism and transport.

The scientists used a strategy called positional cloning both to locate fat free in the zebrafish genome and to determine its sequence. They found that the gene shares 75 percent of its sequence with a human gene called ANG2 (Another New Gene 2), and also shares parts of its sequence with a gene called COG8, which
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Contact: Steve Benowitz
steven.benowitz@jefferson.edu
215-955-5291
Thomas Jefferson University
19-Apr-2006


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