Finally, proof of 'good' cholesterol's perks.

By now, most people know that high blood levels of the so-called "good" cholesterol--high-density lipoprotein particles, or HDLs -- help lower the risk of developing atherosclerosis. Epidemiologists established this medical truism through scores of studies showing that people with elevated HDL levels are less likely to suffer heart attacks caused by narrowed arteries. But researchers have never known for sure whether HDLs actually prevent the fatty arterial deposits characteristic of atherosclerosis, or whether the link is simply a clinically useful coincidence.

Now, a research team at Lawrence Berkeley Laboratory in Berkeley, Calif., has demonstrated that mice with an inherited genetic susceptibility to atherosclerosis fail to develop the initial stage of the disease if they are genetically engineered to carry a human gene for HDL. Other researchers say the finding suggests a new strategy for treating people with high levels of "bad" -- lowdensity lipoprotein (LDL) -- cholesterol.

LDLs ferry cholesterol to blood vessel walls, depositing it as fatty streaks. HDLs clear LDL cholesterol from the bloodstream by transporting it to the liver for breakdown and excretion (SN: 9/9/89, p. 171). Until now, however, scientists lacked proof that HDLs remove enough LDL cholesterol to prevent formation of the fatty streaks, which can eventually harden into plaques on vessel walls.

The new evidence that HDLs inhibit the earliest phase of atherosclerosis "supports what people have observed through epidemiology," says study leader Edward M. Rubin. Beverly Paigen, who studies atherosclerosis in mice at the Jackson Laboratory in Bar Harbor, Maine, says the work "provides really direct evidence that increasing the level of HDLs . . . will give protection against heart disease."

Rubin and his colleagues inserted the human gene for HDLs' primary protein into mice that ordinarily develop telltale fatty streaks in their arteries when fed a high-fat diet. HDL particles contain equal parts of protein and cholesterol; the protein component consists mainly of apolipoprotein A-1 (apo A-1).

The team reports in the Sept. 19 NATURE that the transgenic mice produced nearly three times more apo A-1 than control mice. The high apo A-1 levels prevented fatty arterial streaks even in engineered mice fed high-fat "cookies" made of mouse chow and large amounts of dairy butter. Fatty streaks did develop in engineered mice receiving ultra-high-fat cookies containing cocoa butter, but these deposits covered only one-eighth as much area as those of control mice on the same diet.

The apo A-1 increase, which in turn elevated total levelsof HDLs, "had a very profound effect" in preventing fatty streaks, Rubin concludes. But he cautions that the streaks are only the precursors of life-threatening atherosclerotic plaques. Researchers need to conduct longer studies to show that apo A-1 prevents plaque formation, he says.

In the meantime, Paigen predicts the new work will spur researchers to develop drugs that can raise levels of HDLs. Current drugs that can raise levels of HDLs. Current drug treatments that lower the good cholesterol along with the bad "may not be the optimal kind of therapy," she says. "We really want something that will lower LDL cholesterol and leave the HDL where it is or raise it."