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Scientists uncover gene mutation key to cholesterol control

By Wai Lang Chu , 20-Apr-2006

Researchers think they have found a gene, which when disrupted interferes with the ability to absorb lipids through the intestine. The discovery has added to new insights into mechanisms behind lipid and cholesterol processing, and in turn, the potential development of new cholesterol controlling drugs.

High cholesterol has been a consequence for an increasingly sedentary lifestyle, which has become familiar to those living in the industrialised nations. New drug treatments that can control cholesterol will serve to meet a desperate need in which almost 30m people worldwide require.

"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," said Dr. Shiu-Ying Ho, Jefferson Medical College researcher.

"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."

Ho and his colleagues explained that disrupting the gene interferes with the ability to absorb lipids through the intestine.

Previous experiments by the team demonstrated that zebrafish died when they were about a one and half weeks old because of this defect, even though they looked normal and swallowed 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 per cent 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 gene seems to be some sort of regulator that affects trafficking of lipids of cells through the gut," said fellow researcher Dr. Steven 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," he said.

Current treatments to lower or control cholesterol fall into four categories. The main two being HMG-CoA inhibitors, often called "statins," which have become the most effective cholesterol lowering agents available and in recent years have received increased attention for additional side effects beyond helping patients with high cholesterol.

Drugs in this group include: Lipitor (atorvastatin); Baycol (cerivastatin); Lescol (fluvastatin); Mevacor (lovastatin); Pravachol (pravastatin); Zocor (simvastatin); and the newest approved drug Crestor (rosuvastatin).

Bile acid sequesterants act by binding with the bile produced by the liver. Bile aids digestion and absorption of fats By blocking the fat digestion, bile acid sequesterants prevent the cholesterol formation. Drugs in this class include: Questran (cholestyramine), Colestid (colestipol); and Welchol (colesevalam).

Fibric acid derivatives include Atromid-S (clofibrate); Lopid (gemfibrozil); and Tricor (fenofibrate) and Niacin, or vitamin B-3, are the other two.

The study appears in the April issue of the journal >Cell Metabolism,

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