Research by Russell DeBose-Boyd, Helen Hobbs, and Peter Tontonoz (l-r) on how the body manages cholesterol is revealing new targets for cholesterol-lowering drugs.

“This is one of the most tightly regulated systems in biology,” says Joe Goldstein of the University of Texas (UT) Southwestern Medical Center at Dallas. Goldstein, an HHMI Trustee, shared the 1985 Nobel Prize in Physiology or Medicine with Michael Brown for their discoveries about cholesterol metabolism. “It’s regulated at so many levels, in so many ways that there’s no shortage of questions about how it works,” he says. That means no shortage of potential drug targets.

Goldstein, Brown, and a handful of other HHMI scientists are still piecing together the full picture of how the human body manages cholesterol. In the process, they’re revealing new ways to stop atherosclerosis and heart attacks: by controlling cholesterol production, absorption, and the immune system’s response.

Finding Balance

Despite its bad rap, cholesterol isn’t harmful in moderation. “It’s absolutely required,” says cholesterol researcher Russell DeBose-Boyd, an HHMI early career scientist at UT Southwestern who was a postdoc in the Brown–Goldstein lab. The human body needs cholesterol to function properly—it’s integrated into cellular membranes, in bile it aids digestion, and it plays a key role in the connections between neurons in the brain. But too much cholesterol is toxic for a cell and for the body as a whole. So cells have a complex feedback system to regulate cholesterol levels. The body can make cholesterol, absorb it from food digested in the gut, move it around, and excrete it as bile.

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At any given point, each of these processes can be turned up or down depending on a cell’s needs. “If the cell is deprived of cholesterol, you turn on uptake, and you turn on synthesis,” says DeBose-Boyd. “When the demands are met, synthesis and uptake are both turned off.” But when cholesterol levels from the diet get too high, the body’s system to deal with it becomes overloaded, and molecules idle dangerously in the arteries.

Statins work by halting cholesterol production in cells. They do it by blocking hydroxymethylglutaryl-CoA (HMG-CoA) reductase, an enzyme that carries out an early step of cholesterol synthesis. But the cell reacts to those falling cholesterol levels by making more reductase in an attempt to revive cholesterol synthesis.

“Statins are basically inducing accumulation of the very protein they’re targeting,” says DeBose-Boyd. “We could improve their effectiveness if we can stop that accumulation.” That’s his lab’s goal.

When they are replete with cholesterol, cells not only stop producing HMG-CoA reductase, they also speed up the enzyme’s degradation. In cells deprived of cholesterol and other sterols, reductase molecules stick around, churning out cholesterol, for an average of 10 or 11 hours, says De-Bose Boyd. But with lots of cholesterol around, reductase survives only about an hour.

DeBose-Boyd wants to coax cells to turn on this degradation process even in the low-cholesterol state induced by statins. This would prevent the reductase buildup that limits the drugs’ effectiveness.

“It looks like there is a switch for this whole cholesterol system where it’s either on or it’s off,” says Goldstein, just down the hall from DeBose-Boyd’s lab. “Understanding this switch is really fundamental to understanding the system.” HMG-CoA reductase is normally located on the outer membrane of a cell’s endoplasmic reticulum (ER), a packaging center that directs newly made proteins to their destinations in the rest of the cell.

DeBose-Boyd discovered that in times of high cholesterol, a protein called Insig binds to reductase and removes it from the ER, according to work published June 2010 in the Journal of Biological Chemistry. From there, the reductase ends up in lipid droplets. “They’re basically little balls of fat in the cell,” he says. Exactly how this happens, he’s not sure, but somewhere in the lipid droplet or the cell’s watery cytosol, the reductase is broken into pieces, no longer functional.

DeBose-Boyd’s lab has also revealed that it’s not cholesterol that triggers Insig to bind to reductase and ship it out of the ER. It’s a molecule related to cholesterol, called dihydrolanosterol (DHL). Because it’s not identical to cholesterol, DHL can potentially turn on HMG-CoA reductase degradation without the risk associated with increasing cholesterol levels.

Photos: DeBose-Boyd: UT Southwestern Medical Center at Dallas, Hobbs: UT Southwestern Medical Center at Dallas, Tontonoz: Paul Fetters

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