'Good' lipoprotein shows its bad side.

In the old days, it was easy to tell the hero of a Western (he wrote white) from the villain (in black). Likewise, scientists could distinguish "good" lipoproteins, or fat-transporting substances, from "bad" ones by the density of these lipid-laden particles. High-density lipoproteins (HDL) -- the good guys -- ferried cholesterol away from artery walls to the liver for disposal, while low-density lipoproteins (LDL) deposited lipids, which could clog arteries.

Cardiologists urge their patients to exercise and eat healthful foods in order to lower LDL and raise HDL cholesterol counts, thereby reducing the risk of heart disease.

But Westerns aren't simple anymore, and neither is the lipoprotein story. "It's more complicated than we thought," says Aldons J. Lusis, a geneticist at the University of California, Los Angeles.

Using genetically engineered mice, he and his colleagues have discovered that large amounts of HDL containing apoliproprotein A-II actually increase the chances of developing coronary artery disease. "It clearly demonstrates that the HDLs are heterogeneous and that different HDL particles have different functions," he adds.

This not-so-good HDL protein usually coexists with another protein, called apolipoprotein A-I, in particles. Other scientists had shown that excess apolipoprotein A-I reduces the risk of atherosclerosis in mice.

To assess apolipoprotein A-II, the UCLA group created transgenic mice that contain about 10 copies of the gene specifying this molecule and consequently produce excess apolipoprotein A-II. The researchers then fed these mice either a low-fat or high-fat diet.

Even on a low-fat diet, the transgenic mice wound up with two to three times more HDL and total cholesterol than nontransgenic mice. The high-fat diet roughly doubled these cholesterol concentrations in the transgenic mice, UCLA's Craig H. Warden, Lusis, and their colleagues report in the July 23 SCIENCE.

More important, high concentrations of HDL cholesterol did not protect against atherosclerosis, says Lusis. Normally, mice on low-fat diets do not accumulate the fat-filled foam cells along vessel walls that lead to clogged arteries. But examination of the aortas of the transgenic mice revealed that this buildup occurred despite high HDL, implying that apoplipoprotein A-II may do real harm in addition to interfering with apolipoprotein A-I's good work, says Lusis. Also, the high-fat diet led to bigger buildups in transgenic mice.