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K-State Today

February 12, 2019

University of Texas Southwestern Medical Center professor to speak Feb. 13

Submitted by Biochemistry and Molecular Biophysics

Luke I. Szweda, professor of internal medicine at the University of Texas Southwestern Medical Center, will be the featured speaker for the Biochemistry and Molecular Biophysics Seminar on Feb. 13. He will present "Metabolic Determinants of Cardiac Disease and Renewal" at 4 p.m. in 120 Ackert Hall.

Szweda earned his doctorate in chemistry from the University of California, Los Angeles in 1990 under Daniel E. Atkinson. Following his degree, he served four years as a postdoctoral fellow with Earl R. Stadtman at the NIH National Heart, Lung, and Blood Institute with an NIH Intramural Research Training Award. He began his professional career in 1995 at Case Western Reserve University in Cleveland, rising from assistant to associate professor. During his 10 years there, he received an AHA Established Investigator Award, 2000-2004. He also began a 12-year association with the Université Pierre et Marie Curie in Paris, France, as a visiting professor. In 2005, he left Case Western to be an associate member of the Free Radical Biology and Aging Research Program at the Oklahoma Medical Research Foundation in Oklahoma City, moving to the position of chairman and member of the Aging and Metabolism Research Program in 2007.

Also during this time, he was an adjunct professor of biochemistry and molecular biology at the University of Oklahoma Health Sciences Center. In 2010, he was awarded the Hille Family Foundation Chair, which he held for seven years. In 2013 he was elected an American Association for the Advancement of Science fellow. He began his current position with UT Southwestern in 2017. Along with the AAAS, he is currently a member of the American Chemical Society, American Society of Biochemistry and Molecular Biology, and the American Heart Association.

Presentation abstract: Obesity is an independent risk factor for the development of cardiac hypertrophy and heart failure. This is alarming given that the fraction of the U.S. population that is obese has tripled in the past 25 years, with a third of the population now classified as obese. In the heart, obesity is associated with the inability to appropriately use glucose, heavy reliance on fatty acids for energy production and oxidative stress. Each of these alterations has been implicated in the development of cardiac hypertrophy, a precursor for heart failure. However, molecular events that trigger and mechanistic links between changes in metabolism, oxidative stress, and obesity-induced cardiac hypertrophy have not been defined and thus tractable intervention remains elusive. The mitochondrial enzyme pyruvate dehydrogenase, or PDH, is a key regulatory point in glucose oxidation, committing glucose-derived pyruvate for energy production. Phosphorylation of PDH inhibits the enzyme and is catalyzed by three isoforms of pyruvate dehydrogenase kinase (PDK1, -2, -4) in the heart, while dephosphorylation and activation of PDH is catalyzed by two pyruvate dehydrogenase phosphatases. Mice fed a high-fat diet become obese and develop cardiac hypertrophy. Using this model we have discovered that PDK4-dependent inhibition of PDH initiates loss of cardiac glucose utilization, ensuring heavy reliance on fatty acids for energy production and enhanced mitochondrial-derived oxidative stress. Our laboratory is investigating the specific role of PDH inhibition in obesity-induced hypertrophy. We are also developing novel strategies, based on our finding that PDK4 can be rapidly degraded by the Lon protease, to mitigate the adverse impact of obesity on the heart. Our studies are therefore designed to identify targets, time frames, and barriers for therapeutic approaches that seek to delay the onset and reduce the severity of obesity-induced cardiac hypertrophy.

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