The University of Texas Southwestern Medical Center
Dr. Mangelsdorf is also a professor and chair of pharmacology at the University of Texas Southwestern Medical Center, where he holds the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology.
Nuclear Receptor Signaling Pathways and Metabolism
David Mangelsdorf didn’t set out to study obesity and metabolic syndrome—the topics that consume roughly 80 percent of his lab’s resources. His lab’s forays into mouse physiology, host–parasite relationships, and cancer, for that matter, weren’t intellectual pursuits that he intentionally chose either. He was just following the science.
“To me, it’s always about where the science takes you,” Mangelsdorf says. “I’ve never picked a physiologic topic, disease, or pathway to focus on. I’d much rather pick something that is unknown and see where the science leads me. It’s often in directions that are totally unexpected.”
Trained as a biochemist and molecular biologist, Mangelsdorf expected to spend his career on molecular scavenger hunts—tracking down the components of the pathways that turn genes on and off in a cell’s nucleus. It was a pursuit born out of time spent as a postdoctoral fellow in HHMI investigator Ron Evans’s lab at the Salk Institute for Biological Studies. One focus of the lab at the time was identifying nuclear receptor proteins that turn genes on and off when they meet up with a trigger molecule known as a ligand. These pathways are the means by which hormones have their effects, and hundreds of “orphan” nuclear receptors—receptors whose functions and ligands are unknown—have been identified.
“We are ligand hunters,” he says. “Our laboratory is on a treasure hunt to understand the hormonal ligands for orphan nuclear receptors.”
Serendipity played a role in focusing Mangelsdorf’s science when he went to the University of Texas (UT) Southwestern Medical Center—a mecca for the study of cholesterol and lipid metabolism—to start his own lab. In the Evans lab, he had cloned a nuclear receptor called RXR and discovered that a derivative of vitamin A is the ligand for it. RXR is crucial for mediating the effects of vitamin A. When Mangelsdorf arrived at UT Southwestern, he went to work on another orphan nuclear receptor, LXR. His lab discovered that a cholesterol derivative serves as the ligand for LXR. As it turns out, LXR plays a significant role in regulating cholesterol.
“I was never expecting to work on cholesterol metabolism even though that is a long- established focus of inquiry here at UT Southwestern,” he says, noting that UT’s Michael Brown and Joseph Goldstein won the Nobel Prize for Medicine in 1985 for their groundbreaking work in this field.
Fast on the heels of the LXR discovery, Mangelsdorf determined that bile acids are the ligands for an orphan receptor called FXR. What’s more, the two receptors work in tandem to control and reset lipid metabolism after a meal.
“It was at this point that I made probably the best move of my career—I recruited Steven Kliewer, a former colleague from the Evans lab who had gone to work at GlaxoSmithKline,” Mangelsdorf says. “Like Brown and Goldstein, we run a joint lab, working on how these receptors regulate metabolism.”
Mangelsdorf and Kliewer have found that the receptors not only function in the hormone- stimulated pathway, but they also regulate other hormones that help an organism adjust to rich and lean times by controlling whether it stores fat or burns it. Their work on these receptors has generated insights into obesity and metabolic syndrome—a constellation of conditions that includes obesity, type II diabetes, hypertension, and cardiovascular disease. His discoveries of these receptors are providing significant new targets for drugs to battle these conditions. While the work is important, it’s not enough to sate his curiosity.
“I’m not satisfied just studying obesity and metabolic syndrome,” Mangelsdorf says. “But I’m always pushing for the unknown and looking for the next new thing.”
To temper the sometimes distracting urge to discover new things and prevent himself from “becoming a jack of all trades and the master of none,” Mangelsdorf says he relies on a bit of “intuition” to choose projects where “something makes sense and is exciting.” It was just such an intuition that steered him into exploring the parasite–host relationship.
Because orphan nuclear receptors had been identified only in vertebrates, Mangelsdorf decided to try to find one in an invertebrate such as the commonly studied, free-living nematode Caenorhabditis elegans.
“I thought the C. elegans project would be a one-off,” Mangelsdorf says. “We’d notch one of these invertebrate orphan nuclear receptors in our belt and that would be it.”
Instead, the work has led Mangelsdorf’s lab to study parasitic worms. The team found an orphan nuclear receptor that controls the worm’s development, from larva to adult. This receptor’s hormonal ligand triggers the worm to feed and develop. In the absence of stimulation by that hormone, the worm enters a “resting state” called dauer diapause. C. elegans nematodes enter the dauer diapause state when they sense they have a scarce food supply.
Dauer diapause is similar to the infective state of parasitic nematodes such as hookworms. In the infective state, hookworms are stalled as larvae until they reach the host’s intestine, where they feed and mature. Mangelsdorf has started to see evidence that the parasitic nematode is incapable of producing the hormone that triggers development. It relies, instead, on the host to help it produce the hormone. This allows the hookworm to recognize when it is in the host.
In addition to exploring parasitic worms, Mangelsdorf has moved from molecular genetics to mouse genetics and physiology to understand these orphan receptor pathways. He’s even beginning to examine the role orphan receptors may play in cancer. He sees his eagerness to explore new avenues as the basic calling of a scientist. Still, he finds it important that his work reach beyond scientific curiosity. “Our work is clearly focused on doing something that is relevant to humanity,” says Mangelsdorf. “I like that our science can benefit people.”