Dr. Brian DeBosch, a physician scientist at the Indiana University School of Medicine, is making significant progress in understanding the molecular origins of fatty liver disease, a prevalent cause of liver failure in the United States. His research has identified the critical role of the urea cycle in the development of fatty liver disease, paving the way for potential new medications to treat this currently incurable condition. By uncovering the connection between defects in the urea cycle and the development of fatty liver disease, his findings shed light on the mechanisms underlying this condition.
In a study published in Cell Metabolism, Dr. DeBosch found that defects in the urea cycle lead to secondary impairment in the tricarboxylic acid (TCA) cycle, a key pathway for energy metabolism. This disruption results in inefficient calorie utilization and excessive fat storage in the liver, leading to inflammation and fibrosis, which contributes to the progression of the disease. Given that there are no approved treatments for pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), his research is focused on addressing this urgent need.
Collaborating with Dr. Yin Cao at Washington University in St. Louis, Dr. DeBosch analyzed blood metabolites from a large cohort of healthy patients, revealing that certain metabolites associated with nitrogen and energy metabolism can predict the risk of severe liver diseases, even in healthy individuals. This translational study, supported by mouse research, underscores the critical role of the urea cycle in understanding severe liver diseases. Dr. Cao emphasized that the discovery offers promise for breakthroughs in the prevention and treatment of MASLD and MASH, which are significant health concerns associated with metabolic conditions and an increased risk of various cancers.
In a subsequent study published in Cell Reports Medicine, Dr. DeBosch and his team demonstrated that administering an enzyme called pegylated arginine deiminase (ADI-PEG 20) significantly improved symptoms of fatty liver and obesity in mice, pointing towards potential future therapies. Their findings suggest that targeting nitrogen handling in the liver, related to the urea cycle, could be an effective treatment approach. Additionally, giving mice a precursor to adenine dinucleotide (NAD+), an intermediary that supports TCA cycle function, also improved function in their study models. Dr. DeBosch plans to further explore the effects of ADI-PEG 20 and NAD+ to investigate their molecular connections and identify targeted treatments for fatty liver disease.
Recently joining the IU School of Medicine, Dr. DeBosch leads the nutrition and molecular metabolism research program at the Herman B Wells Center for Pediatric Research. He also serves as the co-division chief of gastroenterology, hepatology, and nutrition at Riley Children’s Health. His expertise in gastroenterology and nutrition allows him to advance the understanding of gut determinants of metabolic diseases and develop innovative treatments for pediatric patients. Dr. DeBosch is excited about collaborating with physicians and scientists at the Wells Center to improve pediatric health outcomes in Indiana and beyond, contributing to the future of pediatric health research.
Dr. DeBosch’s research focuses on diseases such as fatty liver disease, cardiovascular disease, and Type 2 diabetes, aiming to enhance the understanding of these conditions and develop effective treatments. His work at the IU School of Medicine allows him to continue preparing the next generation of experts in the field while making innovative contributions to pediatric health research. By exploring the molecular connections between the urea and TCA cycles and developing targeted treatments for fatty liver disease, Dr. DeBosch is poised to make significant strides in improving outcomes for pediatric patients and advancing the field of pediatric health.
