From a recent study published in Cell Metabolism, insights reveal a vital connection between the urea cycle and the development of fatty liver disease, a leading cause of liver failure. Brian DeBosch, MD, PhD, co-division chief of gastroenterology, hepatology and nutrition at Riley Children’s Health and professor of pediatrics at Indiana University School of Medicine, spearheaded the research, identifying how defects in the urea cycle–a crucial process for detoxifying ammonia–contribute to the progression of fatty liver disease. As a result, findings could signify new therapies aimed to treat the severe condition in children.
The current research builds upon Dr. DeBosch’s existing work, in collaboration with Yin Cao, ScD, MPH of Washington University in St. Louis, where he discovered that urea cycle defects can impair the tricarboxylic acid (TCA) cycle, an essential pathway for energy metabolism, leading to inefficient calorie utilization and excessive fat storage in the liver. In turn, this can progress to liver failure due to the formation of inflammation and fibrosis. The study highlights the importance of understanding these metabolic pathways to develop effective treatments for fatty liver disease, particularly in pediatric patients, where the disease can be more prominent and aggressive.
As pediatric fatty liver disease, including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), gradually increases, Dr. DeBosch’s research aims to mitigate the progression of the disease by finding new therapies that are safe for young patients because presently, there are no approved treatments aimed to treat children.
“I want to explore the best pathways to target these defects so future drugs leveraging this biology can be more effective and precise in treating individuals with fatty liver disease,” Dr. DeBosch said.
Additionally, while at Washington University in St. Louis, the study analyzed blood metabolites from a pool of 106,000 individuals, where the findings, supported by mouse research, showed that specific metabolites related to nitrogen and energy metabolism could predict the risk of severe liver diseases, even in those without apparent health issues. This suggests that early detection and targeted intervention could be key to preventing fatty liver disease in children.
While the study in Cell Metabolism raised the idea that the cell’s ability to process arginine is a protective mechanism against MASLD and MASH, another recent study published in Cell Reports Medicine showed a direct application of this new knowledge. In this study, Dr. DeBosch and his team found that obese mice treated with an enzyme preparation that breaks down arginine, pegylated arginine deiminase (ADI-PEG20), improved fatty liver and obesity, promising the translational potential of this discovery in patients with obesity and fatty liver disease.
“Pediatric fatty liver disease can be much more aggressive and more difficult to treat than the adult forms of the disease,” DeBosch said. “Because there are no approved treatments for pediatric MASLD and MASH, our research is focused on addressing this incredibly urgent need.”
Ahead of the research, Dr. DeBosch’s next plans will explore molecular connections between the urea cycle and the TCA cycle, striving to develop more effective treatments for fatty liver disease.
A nationally recognized leader in basic science research, Dr. DeBosch is a primary investigator of three R01 awards. With a laboratory focused on fatty liver disease, cardiovascular disease and Type 2 diabetes, Dr. DeBosch is passionate about ongoing research, finding therapies and treatments to improve outcomes for patients.