PAGE 4 OF 4
Foam cells are the first sign of an atherosclerotic plaque. The foamy macrophage produces inflammatory molecules and recruits other immune cells to the site, setting up an inflammatory response, a hallmark of coronary artery disease. “The reason the plaque eventually gets so big and complicated is that the macrophage talks to and recruits other cell types,” says Tontonoz.
But what scientists have struggled to understand is why the macrophage recruits inflammatory molecules when it fills with cholesterol. When the macrophage eats other foreign material, it clears them with no inflammation.
Tontonoz has an answer: a protein called LXR. Originally identified by HHMI investigator David Mangelsdorf, of UT Southwestern, LXR switches between an inactive form, in the presence of low cholesterol, and an active form, in the presence of high cholesterol. In its active form, LXR causes the cell to pump cholesterol out and stop taking cholesterol in.
There are different versions of LXR in different cell types, including macrophages. Mangelsdorf and Tontonoz published a 2003 paper showing that LXR also has anti-inflammatory effects. Tontonoz has since discovered that mice without LXR are more susceptible to a host of diseases, including listeria and tuberculosis. Other studies have shown that drugs increasing the activity of LXR in macrophages have the potential to stop the formation of a foam cell—by pumping cholesterol out—and to decrease arterial inflammation. The combination could stop atherosclerosis.
As Tontonoz has explored the pathway of LXR, he’s also discovered how it arrests cholesterol input, and it’s a familiar mechanism: degradation. In a July 2009 paper in Science, Tontonoz reported that one of the proteins that LXR turns on is a protein called Idol. Idol in macrophages has the same job as Hobbs’s PCSK9 in the liver—degradation of LDL receptors. So Idol, like PCSK9, could be a target for new pharmaceuticals. Already, compounds activating LXR are in the pharmaceutical pipeline.
Pieces of the Puzzle
For every 10 milligrams per deciliter of blood that you decrease your LDL, you have a 10 percent decrease in coronary heart disease risk, says Hobbs. Statins have been an effective way to achieve this LDL reduction, but for some patients, they’re not effective enough to stop heart disease. The network of proteins and genes that regulate cholesterol in the body is complex and far-reaching. Statins affect only one part of this system.
The next cholesterol drug—be it a compound that blocks PCSK9, degrades HMG-CoA reductase, or turns on LXR—will likely be used in concert with statins to come at the problem from two angles.
You can’t predict which aspect of the field will lead to the next breakthrough, says Goldstein. “You have to wait and see. But the important thing is to keep looking at this from new angles.”
As scientists forge ahead in probing those new angles and revealing each part of the cholesterol puzzle, they get closer to that next breakthrough, and the promises of the next drug come into focus.