A Worm’s Life: Cholesterol is Key

Like humans, insects and worms need cholesterol; unlike humans, they can’t make it themselves. Their need for cholesterol may be a key to taming certain pathogenic worms and insects, according to research by HHMI investigator David Mangelsdorf. His team discovered that molecules derived from cholesterol are what many pathogenic insects and worms sense that tells them they’re inside a host’s body.

Worms—including the laboratory model organism Caenorhabditis elegans as well as parasites like hookworms and threadworms—go through a stage in their life cycle that’s essentially hibernation. In this suspended state, known as dauer diapause, the worms stop developing and feeding, and the walls of their body thicken to survive environmental challenges. The worms can exit dauer diapause and ramp up their metabolism and reproduction again only when they’re inside their host. Or, in the case of C. elegans and other nonpathogenic worms, in the presence of lots of nutrients.

Mangelsdorf and his colleagues at the University of Texas Southwestern Medical Center knew that a worm could leave the dauer stage only if cholesterol was around. And in 2006 the team found a key hormone derived from cholesterol that activates a receptor called DAF-12. When DAF-12 is mutated, the worms get stuck in the dauer stage.

Mangelsdorf was drawn to DAF-12 because of its similarity to LXR, the sterol-sensing protein in human cells that plays a pivotal role in cholesterol processing. He suspected that a sterol regulated the activity of DAF-12 as well. Indeed, his group discovered that DAF-12 recognizes dafachronic acid, a hormone derived from cholesterol. “It makes sense that this is what’s giving the worm this signal,” says Mangelsdorf. “We have cholesterol and cholesterol metabolites in our bodies, which is where they want to exit the dauer stage.”

When his team gave dafachronic acid to worms that weren’t in an animal’s body, it forced them to come out of dauer diapause too early, thwarting normal development and ending the worms’ life cycle. Furthermore, the group has shown that removing other genes from a worm that are similar to human genes and act downstream of dafachronic acid can have the same effect.

Parasitic worms are responsible for dozens of human, plant, and animal diseases, and Mangelsdorf thinks that understanding the cholesterol-mediated pathway that controls their hibernation state could be key to combating infections. He’s now studying the roles of cholesterol, dafachronic acid, and DAF-12 in a variety of parasites.

-- Sarah C.P. Williams
HHMI Bulletin, May 2011

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