A physician-scientist is making significant progress in deciphering the molecular roots of fatty liver disease, which is a major contributor to liver failure in the U.S.
A physician-scientist from the Indiana University School of Medicine is advancing our understanding of the molecular causes of fatty liver disease, a leading reason for liver failure in the United States. His research highlights the important role the urea cycle plays in the onset of this condition, potentially leading to new treatment options for this currently untreatable disease.
In a recent study published in Cell Metabolism, Brian DeBosch, MD, PhD, a professor of pediatrics at the IU School of Medicine and the study’s lead author, revealed an essential connection between issues in the urea cycle—an important mechanism for clearing ammonia from the body—and the onset of fatty liver disease. This research was conducted during his tenure at Washington University in St. Louis and demonstrated that defects in the urea cycle can cause a secondary dysfunction in the tricarboxylic acid (TCA) cycle, a critical process for energy metabolism. This malfunction leads to poor calorie use and excess fat accumulation in the liver, which can cause inflammation and scarring, further advancing the disease.
“Pediatric fatty liver disease tends to be more aggressive and harder to treat than its adult counterparts,” DeBosch stated. “Compounding this issue is the absence of approved treatments for pediatric MASLD and MASH, even though MASH is rapidly increasing among children. This is why our research is targeting this urgent need.”
The different types of fatty liver disease include metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Both involve the accumulation of excess fat in the liver, which can lead to liver failure if not addressed. The rates of MASLD and MASH are growing quickly in children, where the disease often appears more severely.
DeBosch collaborated with Associate Professor of Surgery and Medicine Yin Cao, ScD, MPH at Washington University in St. Louis for this study. Cao analyzed blood metabolites from a group of 106,600 healthy individuals sourced from the United Kingdom Biobank. Her findings indicated that certain metabolites linked to nitrogen and energy metabolism, as well as mitochondrial health, could forecast the risk of severe liver diseases even in healthy subjects. Cao remarked that the insights gained from this translational study, supported by animal research, highlight the vital importance of the urea cycle in understanding serious liver conditions.
“MASLD and MASH present substantial health challenges that are closely tied to other metabolic disorders and an elevated cancer risk,” she said. “This discovery could lead to breakthroughs in preventing and treating these serious health issues.”
In a 2022 study published in Cell Reports Medicine, DeBosch and his research team found that administering an enzyme known as pegylated arginine deiminase (ADI-PEG 20) significantly alleviated fatty liver and obesity symptoms in mice, providing hopeful insights for future treatments. Their latest research further indicates that targeting nitrogen management in the liver—related to the urea cycle—might offer an effective treatment strategy.
Additionally, their research showed that supplying mice with a precursor to adenine dinucleotide (NAD+), a crucial component that enhances TCA cycle function, improved functionality in their study models. Looking forward, DeBosch intends to further investigate the effects of ADI-PEG 20 and NAD+ and their molecular roles in the urea and TCA cycles.
“I aim to identify the most effective paths to address these defects, so future drugs utilizing this biological knowledge can be more efficient and targeted in treating individuals with fatty liver disease,” DeBosch explained.
DeBosch joined the IU School of Medicine’s Department of Pediatrics in July 2024 to lead a newly established research program focused on nutrition and molecular metabolism at the Herman B Wells Center for Pediatric Research. He is also the new co-division chief for gastroenterology, hepatology, and nutrition at Riley Children’s Health.
“We’re excited to welcome Dr. DeBosch to our team at the Wells Center and eagerly anticipate the innovative contributions he will make to our new research program in nutrition and molecular metabolism,” stated Reuben Kapur, PhD, director of the Wells Center. “His expertise is crucial as we strive to enhance the health and well-being of children throughout Indiana.”
A nationally recognized expert in gastroenterology and nutrition, DeBosch aims to deepen understanding of the gut factors influencing metabolic diseases and develop innovative treatments that improve pediatric patient outcomes. His laboratory focuses on researching conditions such as fatty liver disease, cardiovascular disease, and Type 2 diabetes.
“I’m thrilled to be part of the IU School of Medicine and the Wells Center,” said DeBosch. “This opportunity allows me to work alongside amazing physicians and scientists while helping to train the next generation of leaders in this field. I look forward to contributing to the mission of the center to improve pediatric health outcomes both in Indiana and beyond.”
