DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM

PROJECT SUMMARY/ABSTRACT
Urea cycle disorders (UCDs) are common inborn errors of hepatic metabolism. With improved therapies
such as nitrogen-scavenging agents to prevent elevated ammonia levels, patients with UCDs have increased
survival. However, even in the absence of hyperammonemia, patients with UCDs may have chronic liver
disease. Liver disease in UCDs can manifest as abnormal serum transaminases, hepatomegaly, hepatic
fibrosis, or hepatocellular carcinoma. Among the UCDs, the highest prevalence of chronic liver disease occurs
in argininosuccinate lyase deficiency (ASLD). Importantly, the cause for liver disease in UCDs such as ASLD is
unknown, and liver disease has not been prevented by standard therapies. Moreover, there are no therapeutic
strategies specifically targeting liver disease in ASLD or other UCDs.
One common histopathologic finding in ASLD and other UCDs is excess hepatic glycogen deposition.
However, the mechanism underlying hepatic glycogen accumulation and its consequences on hepatic function
in UCDs are unknown. Hepatic glycogen deposition is associated with liver disease in glycogen storage
disorders and diabetic glycogenic hepatopathy. Thus, our central hypothesis is that urea cycle dysfunction and
accumulation of ammonia and other toxic metabolites disrupt hepatic energy metabolism, including glycogen
metabolism, and cause liver disease in UCDs. Studies using current mouse models of ASLD and other distal
UCDs have been complicated by the small size and shortened lifespan. To overcome this challenge and
facilitate our proposed studies, we have manipulated mouse models of ASLD and citrullinemia to extend the
lifespan and improve growth. For the proposed studies, we will use biochemical studies, genetic manipulation
and stable isotope studies in these mouse modes to address the following questions: 1) What is the
biochemical basis of hepatic glycogen accumulation in ASLD? 2) Does normalization of hepatic glycogen
levels prevent liver disease in ASLD?
Insights from these studies have the potential to have significant impact on our understanding of the
relationship between urea cycle dysfunction and hepatic glycogen metabolism. In addition, the results may
inform chronic management strategies for patients with UCDs and may lend insights into new treatment
approaches for this group of disorders. On broader terms, our studies may elucidate mechanisms that
contribute to the regulation of hepatic glucose flux in more common disorders of glucose metabolism.

Grant Number: 5R01DK126786-05
NIH Institute/Center: NIH
Principal Investigator: Lindsay Burrage