“If we were to get a drug from this work, it’d have to be designed after DHL,” says DeBose-Boyd. But such a drug is still hypothetical. No pharmaceutical company will pursue it until DeBose-Boyd or others reveal the full picture of how reductase degradation works—the role of the lipid droplets, how DHL mediates Insig, and how the final degradation happens.

Genetic Targets

Other researchers are aiming new drugs at the part of the system that imports cholesterol. When it travels in blood, cholesterol is packaged inside lipoproteins—either low-density lipoproteins (LDL), considered the bad guys for their accumulation in arteries, or high-density lipoproteins (HDL), the “good” lipoproteins that carry cholesterol to the liver for excretion. People with low levels of LDL and high levels of HDL have the lowest chance of atherosclerosis and heart disease. These days, cholesterol reduction is measured by tracking LDL; the role of HDL is not as clear-cut.

For more than three decades, HHMI investigator Helen Hobbs has been tracking down individuals with extreme LDL and HDL levels—either low or high—and analyzing their genetics. Hobbs, a physician and researcher at UT Southwestern, got her start in research with a postdoctoral fellowship in the Brown–Goldstein lab. She hopes to uncover genetic mutations that hint at new drug targets for managing cholesterol. She’s already revealed one promising candidate—a protein that sweeps the bloodstream clear of LDL—and it’s in the pharmaceutical pipeline.

In 2003, a research group in France identified a gene called PCSK9 that helps control LDL levels. Hobbs had already been following the genetics and cholesterol levels of almost 3,500 people as part of the Dallas Heart Study, her large-scale attempt to find genetic causes of heart disease. So her team tested a handful of participants for mutations in the PCSK9 gene. They found them—in 2 percent of their African-American participants. They repeated the work in a larger population and showed that PCSK9 mutations were associated with a 28 percent reduction in LDL and an 88 percent decrease in coronary heart disease.

“Studies like the Dallas Heart Study are absolutely key to this field,” says Joe Goldstein. “The way to find interesting mutations is to find a population and look at those extremes.”

The research team led by Hobbs then relied on basic biochemistry to piece together PCSK9’s function. They discovered that the protein encoded by PCSK9 is required to degrade the LDL receptor—the protein that pulls LDL from the bloodstream into a cell’s interior. Removal of functioning PCSK9 protein is an ideal recipe for treating high cholesterol: LDL receptors increase, LDL in the bloodstream decreases, and atherosclerosis risk drops.

“This is the single biggest story in the translational medicine side of cholesterol research right now,” says Goldstein. “Hobbs has taken PCSK9 all the way from a finding in a population to learn the real importance of the protein to medicine. And now we have a really good drug target.”

Hobbs identified a person in the Dallas Heart Study who has no PCSK9 and appears to be completely healthy, which has reassured pharmaceutical companies about the safety of the protein as a drug target. A PCSK9 inhibitor is now in early phase human studies with the pharmaceutical company Regeneron. It blocks PCSK9 from binding to and degrading the LDL receptor and results in a dramatic reduction in LDL levels.

A Role for Inflammation

Cholesterol build-up causes inflammation too, which is a risk factor for atherosclerosis. That inflammation pathway offers another target for drug developers.

When cholesterol accumulates along artery walls, macrophages—immune cells that recognize foreign material—are the first cells to encounter the clumps. The reaction of the macrophage to the cholesterol can either help clear the artery or make problems worse.

“A macrophage is a scavenger for extracellular garbage,” says HHMI investigator Peter Tontonoz of the University of California, Los Angeles. “And when there are cholesterol deposits, they’re recognized by the macrophage as junk that it wants to clear.” Normally, this is a good thing—macrophages help remove LDL from the artery wall. But when a macrophage is overwhelmed with too much cholesterol to process, it turns into a foam cell—so named because the LDL in its interior looks like foamy bubbles.

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