Snacks for Fat Cats?

No, they're not meant as a tasty alternative to low-calorie cat chow diets. But scientists have created a strain of mice that can't produce cholesterol. The animals are viable, the study shows, because another fat molecule can pick up most of cholesterol's duties.

In spite of its bad press, cholesterol is an important part of our lives. Cell membranes are full of it, enzymes modify it to make sex steroids, and developing embryos rely upon it to grow. In cells, two biochemical pathways convert sterols into cholesterol, and disruption of either one leads to serious human endocrine diseases. Researchers had previously knocked out one pathway in mice and found that the scurriers can't live without it. Now, another group of scientists, led by Elena Feinstein at Quark Biotech in Cleveland, Ohio, have halted the other cholesterol-generating pathway, they report in the 19 December issue of Science.

The team found the gene for a key enzyme, desmosterol reductase, which converts desmosterol to cholesterol, and created mice lacking both copies of the gene. Compared to normal mice, the modified mice had very low levels of cholesterol both in the blood and the liver; they also had about 20% to 60% less total sterols. The team found that desmosterol was the predominant sterol, suggesting that this molecule can take over in the absence of cholesterol. They also discovered that as embryos, the transgenic mice had almost normal concentrations of cholesterol, which they probably received from their mothers and which allowed them to develop normally until birth. As they grew up, however, they developed health problems, including infertility.

The novelty of the results is that "desmosterol seems to be able to fill in for cholesterol," says clinical geneticist Forbes Porter of the National Institute of Child Health and Human Development in Bethesda. The work may help researchers understand why cells bother to make cholesterol instead of using its precursors, he says. Clinical metabolic geneticist Hans Andersson at Tulane University Medical School says the work might not be relevant to human disease because humans with mutations in desmosterol reductase are sick and yet have significant levels of cholesterol, in contrast to the rodents. "Mice may not be the best model of human disorders of sterol BIOSYNTHESIS," he says.

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