91ÑÇÉ«´«Ã½

Two of Russell DeBose–Boyd’s great passions are cholesterol synthesis and cooking. He says that being methodical, disciplined and focused are key ingredients of his approach to both, and this formula has guided his career.

Strong mentorship also has inspired his recipe for success, and he advises trainees on what to look for.

“First, find the right mentor, and that mentor doesn’t have to look like you” he said. “I’ve never had a mentor who looks like me, and yet I’ve had great mentorship. Your mentor needs to give you honest and helpful advice and have a track record of mentoring other successful scientists.”

“Second, build a mentorship team of people you trust who can guide your career and help you in professional development.”

DeBose–Boyd is a researcher and professor of molecular genetics at the University of Texas Southwestern Medical Center. His contributions to unraveling the complex regulation of cholesterol synthesis will be recognized at Discover BMB in March, where he will receive the 91ÑÇÉ«´«Ã½’s 2023 Avanti Award in Lipids.

His colleagues lauded DeBose–Boyd’s expertise, life’s work and collegiality in their letters of support for the award.

Robert Farese Jr. of the Harvard T.H. Chan School of Public Health (a 2022 Avanti Award recipient) described him as “an outstanding colleague, who is always available and eager to discuss ideas and think creatively.”

Tom Rapoport of Harvard Medical School wrote that DeBose–Boyd’s discoveries “have clarified important aspects of lipid metabolism. His work on the regulation of HMG CoA reductase degradation is simply outstanding. The experiments are beautifully designed and executed.”

DeBose–Boyd also serves as an associate editor of the Journal of Lipid Research and a member of the Journal of Biological Chemistry editorial board.

And he offered a few last steps in his recipe for good science: “Ask an interesting, important and impactful question, because at the end of the day we must get our work funded.

“Finally, have fun. Enjoy working with your hands, doing experiments, looking at results, writing papers; enjoy the process of being a scientist.”

How cholesterol regulation is linked to vitamin K2 synthesis

Russell DeBose–Boyd studies the highly regulated enzyme HMG-CoA reductase, the target of life-saving statin drugs that catalyzes a rate-limiting step in cholesterol synthesis. DeBose–Boyd has shown one mechanism for regulation of HMG-CoA reductase involving its sterol-accelerated degradation. He found that degradation of HMG-CoA reductase is inhibited by the protein UBIAD1, which uses geranylgeranyl pyrophosphate to synthesize a form of vitamin K2. Binding of geranylgeranyl pyrophosphate to UBIAD1 enhances HMG-CoA reductase degradation.

Mutations in UBIAD1 that prevent geranylgeranyl pyrophosphate binding lead to the stabilization of HMG-CoA reductase and overaccumulation of cholesterol. In animals, this accumulation results in a corneal disease called Schnyder corneal dystrophy that significantly impairs vision.

When mouse embryos are genetically altered to remove UBIAD1, they do not survive. DeBose–Boyd discovered that this embryonic lethality is not caused by vitamin K2 deficiency but by deficiency in HMG-CoA reductase that results from its enhanced degradation. He identified key residues in HMG-CoA reductase whose mutation blocked degradation and prevented the embryonic lethality associated with UBIAD1 deficiency. These UBIAD1-deficient mice are a novel model of vitamin K2 deficiency, and studying them will show new physiological roles of the vitamin.