RxPG News Feed for RxPG News

Medical Research Health Special Topics World
 Asian Health
 Food & Nutrition
 Men's Health
 Mental Health
 Occupational Health
 Public Health
 Sleep Hygiene
 Women's Health
 Canada Healthcare
 China Healthcare
 India Healthcare
 New Zealand
 South Africa
 World Healthcare
   Latest Research
 Alternative Medicine
 Clinical Trials
 Infectious Diseases
 Sports Medicine
   Medical News
 Awards & Prizes
   Special Topics
 Odd Medical News

Last Updated: Oct 11, 2012 - 10:22:56 PM
Biochemistry Channel

subscribe to Biochemistry newsletter
Latest Research : Biochemistry

   EMAIL   |   PRINT
Lethal Gene Mutation Key to Blocking Cholesterol Processing Uncovered

Apr 20, 2006 - 4:01:00 PM , Reviewed by: Priya Saxena
“The gene seems to be some sort of regulator that affects trafficking of lipids of cells through the gut,”

[RxPG] 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 is known to affect the Golgi apparatus. A change in only one base—one “letter” in the DNA code—results in the lethal mutation in zebrafish.

“The implication is that we can now attempt to screen drugs and look to see if anything can rescue this defect and increase intestinal lipid absorption,” notes Dr. Ho. “We can try to find associated genes, proteins and other partners that are involved in this complex, as well as some of the mechanisms involved. The gene is well conserved across species and no one has discovered its function as yet, which makes it very exciting.”

“The gene seems to be some sort of regulator that affects trafficking of lipids of cells through the gut,” says Dr. Farber. “The next step is to try to understand mechanistically how the protein functions and what other genes it works with. Once we understand that, then we can potentially design drugs. A number of genes that regulate lipid metabolism have yet to be determined, and there’s much to learn about how animals process lipids.”

In earlier work at Jefferson, reported in Science, the research team 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, lipid processing in transparent zebrafish embryos.

They created random genetic mutations in zebrafish by exposing males to a chemical agent, then breed families harboring the resulting mutations. They then fed the fluorescent molecule to resulting zebrafish embryos carrying various mutations and watched it light up in the digestive tract, liver and eventually the gallbladder, examining the pattern of fluorescence. The scientists subsequently screened for alterations in lipid processing.
One major advantage of the zebrafish model is that it allows scientists to do “forward genetics.” In this case, researchers look for a change in function, such as lipid metabolism, and then figure out what causes this effect. In reverse genetics, in contrast, researchers “knock down/out” a known gene and watch what effect it has on an organism.

Publication: April issue of the journal Cell Metabolism
On the web: http://www.jeffersonhospital.org/ 

Advertise in this space for $10 per month. Contact us today.

Related Biochemistry News

Subscribe to Biochemistry Newsletter

Enter your email address:

For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

Top of Page

Contact us

RxPG Online



    Full Text RSS

© All rights reserved by RxPG Medical Solutions Private Limited (India)