Scientists discover key gene impacts liver energy storage, affecting metabolic disease risk

PHILADELPHIA (May 16, 2025) – A new study published in Science Advances reveals that a single gene plays a big role in how the liver stores energy, a process that's critical for overall health and for managing diseases like type 2 diabetes. Led by Penn Nursing’s Kate Townsend Creasy, PhD, Assistant Professor of Nutrition Science in the Department of Biobehavioral Health Sciences, the research focuses on the PPP1R3B gene. This gene tells the liver how to handle energy: store it as glycogen (a form of sugar) or triglycerides (a type of fat).

The research team found that when the PPP1R3B gene is more active, the liver tends to store more energy as glycogen. The liver stores more energy as fat when the gene is less active. This shift between glycogen and fat storage is crucial because it affects how the body manages blood sugar and fat levels.

Large scale genomics studies in humans have reported that mutations in the PPP1R3B gene are associated with several metabolic conditions, including type 2 diabetes and fatty liver disease. However, it was unclear how the gene was involved in these conditions.

“Our research shows that PPP1R3B is like a control switch in the liver,” said Creasy. “It directs whether the liver stores energy for quick use in the form of glycogen or for longer-term storage as fat. We also saw changes in how efficiently mice and cells with genetic manipulations of PPP1R3B could use either glucose or fat for energy. This discovery could help us find new ways to help people with metabolic diseases with precision nutrition approaches, based on their genetics.”

Co-authors from the Perelman School of Medicine include: Minal B. Mehta, Joseph Park, David Zhang, and Swapnil V. Shewale (all based in the Department of Genetics), Carolin V. Schneider (Division of Translational Medicine and Human Genetics), John S. Millar (Institute for Diabetes, Obesity, and Metabolism), Marijana Vujkovic (Division of Translational Medicine and Human Genetics and the Institute for Diabetes, Obesity, and Metabolism), Nicholas J. Hand (Department of Physiology), Paul M. Titchenell (Institute for Diabetes, Obesity, and Metabolism and the Department of Physiology), Joseph A. Baur (Institute for Diabetes, Obesity, and Metabolism and the Department of Physiology), and Daniel J. Rader (Division of Translational Medicine and Human Genetics in the Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism). The National Institutes of Health supported this research.

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