Fighting Fatty Liver Disease: Uncovering the Cellular Roots
An Indiana University School of Medicine physician scientist is at the forefront of groundbreaking research into the molecular origins of fatty liver disease, a pervasive and potentially life-threatening condition affecting millions of individuals in the United States. Through his in-depth exploration of the critical role played by the urea cycle in the development of this disease, Dr. Brian DeBosch is paving the way for innovative treatments that could revolutionize the current approach to managing this challenging condition.
In a recent study published in the esteemed journal Cell Metabolism, Dr. DeBosch, a professor of pediatrics at the IU School of Medicine, shed light on a crucial connection between defects in the urea cycle – a vital process involved in detoxifying ammonia in the body – and the onset of fatty liver disease. Conducted during his tenure at Washington University in St. Louis, the study unveiled how these urea cycle deficiencies lead to secondary impairments in the tricarboxylic acid (TCA) cycle, a key pathway governing energy metabolism. This disruption ultimately results in inefficient calorie utilization and excessive fat accumulation in the liver, triggering inflammation and fibrosis that hasten the progression of the disease.
“Pediactric fatty liver disease can be particularly aggressive and challenging to manage compared to its adult counterparts,” explains Dr. DeBosch. “With the lack of approved treatments for pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), there is an urgent need for new therapeutic strategies to address this pressing health issue.”
The incidence of MASLD and MASH is escalating at an alarming rate among children, presenting a growing public health concern. To unravel the molecular underpinnings of these conditions, Dr. DeBosch collaborated with Associate Professor Yin Cao of Washington University in St. Louis, who conducted an analysis of blood metabolites from a cohort of 106,600 healthy individuals from the UK Biobank. Her findings highlighted specific metabolites related to nitrogen and energy metabolism, as well as mitochondrial function, that could predict the risk of severe liver diseases even in seemingly healthy subjects. This translational study, supported by mouse research, underscored the pivotal role of the urea cycle in deciphering the complexities of severe liver disorders.
“Meticulous attention to the urea cycle is paramount in our understanding of MASLD and MASH, which are intricately linked to other metabolic conditions and heightened risks of various cancers,” states Cao. “This discovery opens up promising avenues for enhancing the prevention and treatment of these significant health threats.”
Building on these critical insights, Dr. DeBosch and his team delved deeper into potential therapeutic interventions, as demonstrated in a 2022 study published in Cell Reports Medicine. Their research showcased the efficacy of administering pegylated arginine deiminase (ADI-PEG 20), an enzyme that significantly alleviated symptoms of fatty liver disease and obesity in mouse models, offering hope for future treatment modalities. Furthermore, their findings suggested that targeting the nitrogen-handling processes associated with the urea cycle could represent a potent therapeutic strategy for combating this complex disease.
Moreover, their investigations revealed the benefits of supplementing mice with a precursor to adenine dinucleotide (NAD+), a key intermediary crucial for TCA cycle function, in enhancing metabolic processes within their study models. Looking ahead, Dr. DeBosch plans to delve into the molecular interactions connecting ADI-PEG 20 and NAD+ with the urea and TCA cycles, paving the way for more precise and effective drug therapies targeting these defects.
“I am committed to exploring optimal pathways for addressing these vulnerabilities to develop novel treatments that harness the potential of this biological connection in combating fatty liver disease,” affirms Dr. DeBosch.
In July 2024, Dr. DeBosch joined the IU School of Medicine’s Department of Pediatrics to spearhead the newly established nutrition and molecular metabolism research program at the Herman B Wells Center for Pediatric Research. Additionally, he assumed the role of co-division chief of gastroenterology, hepatology, and nutrition at Riley Children’s Health, further solidifying his dedication to advancing pediatric healthcare outcomes.
“We are thrilled to welcome Dr. DeBosch to our team at the Wells Center and eagerly anticipate the innovative contributions he will bring to our new nutrition and molecular metabolism research program,” expresses Dr. Reuben Kapur, director of the Wells Center. “His expertise will be instrumental in our efforts to enhance the health and well-being of children throughout Indiana and beyond.”
A distinguished expert in gastroenterology and nutrition on the national stage, Dr. DeBosch aims to deepen our understanding of the gut-related factors contributing to metabolic diseases while pioneering transformative treatments that enhance outcomes for pediatric patients. His laboratory’s focal points include researching disorders such as fatty liver disease, cardiovascular disease, and Type 2 diabetes to advance medical knowledge and clinical care.
“I am excited to collaborate with the IU School of Medicine and the Wells Center, where I have the opportunity to work alongside exceptional physicians and scientists while nurturing the next generation of experts in the field,” shares Dr. DeBosch. “I am eager to contribute to the center’s mission of enhancing pediatric health outcomes in Indiana and beyond, making a lasting impact on the future of healthcare.”
With his groundbreaking research into the molecular origins of fatty liver disease and innovative therapeutic approaches, Dr. Brian DeBosch is at the vanguard of a new era in pediatric healthcare, offering hope to countless individuals affected by this challenging condition. Through his unwavering commitment to excellence and compassion, he is transforming the landscape of medical research and paving the way for a healthier future for generations to come.
