Russell DeBose-Boyd, PhD

Tell us a little bit about yourself (current role, background, family, etc.)

I was raised in the small rural southeastern Oklahoma town of Boswell. Soon after completing high school, I began undergraduate studies at Southeastern Oklahoma State University in Durant, OK, where I participated in the Minority Biomedical Research Support program. After obtaining a Bachelor of Science degree in Chemistry, I was accepted into the Department of Biochemistry and Molecular Biology at the University of Oklahoma Health Sciences Center and joined the laboratory of Dr. Richard Cummings. Following the successful defense of my thesis, I joined the laboratory of Drs. Joseph Goldstein and Michael S. Brown at UT Southwestern Medical Center as a postdoctoral fellow and later joined the faculty of the Molecular Genetics department as an Assistant Professor. I am current Professor of Molecular Genetics and hold the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science.

My wife Gwendolyn and I celebrated our 30th wedding anniversary earlier this year and we have two children, Reginald (age 28) and Ryan (age 26), that both reside in the Dallas area.

What was your first encounter with lipids in a research lab setting?

My first encounter with lipids in the research lab setting occurred in 1998 when I began postdoctoral studies in the Brown/Golstein laboratory. As a postdoctoral fellow, I studied the proteolytic activation of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that control expression of genes encoding enzymes required for cholesterol and unsaturated fatty acid synthesis as well as the low density lipoprotein (LDL)-receptor. The focus of my studies was a cholesterol-regulated escort protein called Scap, which mediates translocation of SREBPs from the endoplasmic reticulum to the Golgi apparatus where SREBPs are released from membranes by sequential proteolytic cleavages.

What do you consider to be the greatest breakthrough in lipid research in recent years?

I think the discovery and development of CRISPR/Cas9 techniques and its utilization in generation of genetically manipulated mice is the greatest breakthrough in not only lipid research, but all areas of investigation. Another major breakthrough in lipid research is the utilization of cryogenic electron microscopy (cryo-EM) in determining the molecular structure of membrane proteins. Many proteins and enzymes that regulate lipid metabolism are membrane proteins and the use of cryo-EM to determine the structures of these proteins has provided key insight into their mechanism of action.

Much of your research focuses on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and its role in cholesterol synthesis.

a. Could you briefly describe to the audience the role that HMGCR plays in cholesterol synthesis?

HMGCR is an integral membrane protein of the ER that catalyzes the rate-limiting step in the synthesis of cholesterol and essential nonsterol isoprenoids that are required for normal cell function.

b. And the importance of understanding the underlying mechanism involved?

As the rate-limiting in the cholesterol biosynthetic pathway, HMGCR is subjected to tight feedback regulation through multiple mechanisms that are mediated by certain types of sterols and nonsterol isoprenoids. Elucidating the mechanisms for feedback regulation of HMGCR will disclose how cells sense levels of membrane-embedded lipids and trigger reactions that prevent their potentially toxic over-accumulation.

What influenced you to focus your research on cholesterol synthesis and metabolism?

As a graduate student, I participated in a laboratory journal club where I became familiar with the work of Brown/Goldstein on SREBP pathway. Fortunately, my turn to present a paper in journal club in many cases coincided with a new publication from Brown/Goldstein. I became fascinated with their work, which led me to read most of their early papers dating back to the 1970s. This prompted me to apply to their laboratory for postdoctoral studies and I’ve never left the cholesterol metabolism field.

Your group, in collaboration with Xiaochun Li, recently reported insights into the UBIAD1-mediated protection of HMGCR from ERAD. Could you explain how this insight could lead to enhanced statin efficacy and reduction of atherosclerotic cardiovascular disease?

Statins competitively inhibit HMGCR and reduce cholesterol synthesis in the liver, which stimulates expression of hepatic LDL-receptors that remove LDL from circulation. Although statins can reduce LDL by up to 50%, further reduction is limited because the drugs block synthesis of sterol and nonsterol isoprenoids that mediate feedback regulation of HMGCR. As a result, HMGCR protein markedly accumulates, which partially overcomes inhibitory effects of statins. Our studies indicate that UBIAD1-mediated inhibition of ERAD contributes to the statin-induced accumulation of HMGCR. Together with Dr. Xiaochun Li, we determined the molecular structure of the HMGCR-UBIAD1 complex, which is maintained by a hydrophobic interface formed by transmembrane domains of the two proteins. We postulate that molecules that disrupt this interface will enhance ERAD of HMGCR, preventing its statin-induced accumulation.

What is the best piece of advice you have ever received from someone?

One of the best pieces of advice that I’ve received was from Drs. Brown and Goldstein who told me earlier in my career to work in the laboratory for as long as I can. This was brilliant piece of advice that was vital in the establishment of my laboratory.