Twenty million Americans take statin drugs every day to reduce their levels of "bad" cholesterol—low density lipoproteins, or LDLs. Statins dramatically cut LDL levels for many patients, but this cholesterol drop is limited by a built-in…
Twenty million Americans take statin drugs every day to reduce their levels of "bad" cholesterol—low density lipoproteins, or LDLs. Statins dramatically cut LDL levels for many patients, but this cholesterol drop is limited by a built-in feedback system. This biological loop responds to plummeting cholesterol levels by telling cells to make more cholesterol. Russell DeBose-Boyd wants to find a way around this statin stalemate. To understand this statin impasse, DeBose-Boyd studies HMG-CoA reductase, an enzyme that sets the rate of cholesterol production. Statins block the enzyme, but they also seem to drive up HMG-CoA reductase levels by slowing its natural degradation. When blocked by statins, the accumulating enzyme convinces the cell's sensing system that cholesterol levels are crashing, and the cells respond by attempting to rev up synthesis. "When statins are inhibiting the activity of the reductase, the cell thinks, 'I've got to make more cholesterol,'" says DeBose-Boyd, who is at the University of Texas Southwestern Medical Center. This feedback loop limits the usefulness of statin drugs, but DeBose-Boyd is finding ways to snap the cycle. For instance, he identified a series of proteins that tag reductase for degradation. "But it turns out these proteins aren't really active enough to destroy all the reductase that builds up during statin treatment," he says. If he can find a way to enhance the activity of the degrading proteins and clear more reductase, "that would help statins work better" or even provide an alternative therapy for the roughly 20 percent of patients who resist the effects of statins altogether. DeBose-Boyd, who grew up on a farm in rural Oklahoma, became intrigued by cholesterol early on, beginning with an undergraduate biochemistry class at Southeastern Oklahoma State University where he first learned about the complex enzymatic machinery that produces cholesterol. His interest was further piqued when, through a program for undergraduate science students, he attended a meeting where a speaker detailed old experiments that illuminated the cholesterol synthesis pathway. "I loved that talk, but of course at the time I didn't know I would eventually end up studying cholesterol," DeBose-Boyd says. When he went to the University of Oklahoma Health Sciences Center for graduate school, DeBose-Boyd focused on parasites and glycoproteins, complexes of sugars attached to proteins that trigger the immune system. But his fascination with cholesterol reemerged after his mentor encouraged him to read articles outside the glycoprotein field for a journal club. DeBose-Boyd chose papers from the 1970s by Michael Brown and Joseph Goldstein, the team that won the 1985 Nobel Prize in Physiology or Medicine for their breakthrough in understanding how the body makes cholesterol—the discovery that led to the development of statins. "Every time my turn came up in journal club, I'd present several Brown and Goldstein papers," says DeBose-Boyd. "Those papers are just so classic. They were a joy to read." When it came time to apply for a postdoctoral fellowship, DeBose-Boyd knew exactly where he wanted to work—the lab of Brown and Goldstein. His Ph.D. adviser, Richard Cummings, had worked with the duo and recommended DeBose-Boyd to them. Brown and Goldstein snapped him up. After his arrival, DeBose-Boyd mapped out the molecular interactions that lead to the degradation of reductase. These key steps in cholesterol regulation had stymied researchers for a decade because they are so complex. Brown and Goldstein responded to DeBose-Boyd's success by arranging a research position for him in their lab after his postdoctoral fellowship ended. This three-year window gave him the space to build his own research program to continue studying HMG-CoA reductase and how it regulates cholesterol without the typical stresses that come with a faculty position. "It was protected time," says DeBose-Boyd. He made good use of it by searching for ways to prevent the cholesterol feedback loop from kicking in and sabotaging statins. He's hit on one strategy that just might work—stimulating natural proteins that clear the reductase enzyme, which in turn prevents synthesis of cholesterol. "It helps the statins work better," says DeBose-Boyd. If these insights can be leveraged into new drug therapies, millions of people with coronary artery disease might benefit as a result.