Mouse Model for Inherited Coronary Clogging

Scientists have bred a new kind of mouse that suffers from atherosclerosis when fed a high-fat Western diet. The finding, reported in tomorrow's Science,* offers a model for probing the causes of a human disorder--familial combined hyperlipidemia (FCHL)--that occurs in about 2% of individuals in Western countries and can lead to premature coronary disease.

In an elegantly simple experiment, Alan R. Tall and colleagues at Columbia University bred mice carrying a human gene linked to FCHL with mice lacking several protein receptors that bind to low-density lipoprotein (LDL), a fat molecule that at high blood levels is associated with atherosclerosis. The human gene, apolipoprotein C-III, is linked to elevated blood levels of very low density lipoprotein (VLDL), also a culprit in coronary disease. Thus the mouse offspring had the worst of both worlds: loads of circulating VLDL and a crippled ability to remove LDL from the blood.

Tall's team fed the mice a diet consisting of about 20% saturated fat that was also high in cholesterol. "The big surprise," says Tall, "was that the two genetic defects didn't just add to each other. They were markedly synergistic." The mice had a fourfold increase in VLDL and LDL levels compared to normal mice and developed arterial clogging earlier and more severely than did both normal mice and the genetically engineered hybrids on a regular diet. The finding adds weight to a theory that APOC3 and faulty LDL receptors together play a key role in the elevated lipid levels seen in FCHL, Tall says.

"It's an imaginative study," says Richard Havel, a lipid researcher at the University of California, San Francisco. But APOC3 likely isn't the only villain in FCHL, which is thought to arise from defects in several genes. Still, Havel says, the work "is a step in the right direction." The next step will be to try to breed mice with defects in several genes that mimic the human condition even more closely.

* Science Online subscribers can link to the full text of the Report.

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