# Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency

> **NIH NIH R03** · BAYLOR COLLEGE OF MEDICINE · 2020 · $120,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Urea cycle disorders are common inborn errors of liver metabolism. With improved therapies such as
nitrogen-scavenging agents to prevent elevated ammonia levels, patients with urea cycle disorders have
increased survival. However, even in the absence of hyperammonemia, patients with urea cycle disorders
(UCDs) may have chronic liver disease. This chronic liver disease appears to be more common in
argininosuccinate lyase deficiency (ASLD) as compared to other urea cycle disorders. The hepatic complications
in ASLD range from chronic hepatocellular injury, hepatomegaly, fibrosis, cirrhosis, and possibly hepatocellular
carcinoma. The pathogenesis for liver disease in ASLD and other UCDs remains unknown, and thus, there are
no specific therapies that target this complication.
 As a first step towards developing therapeutic strategies targeting liver disease in ASLD and other UCDs,
we propose to investigate the biochemical basis of liver disease using a mouse model and newly developed
hepatocyte-like cell models for this disorder. Since the enzyme, argininosuccinate lyase, integrates two
fundamental pathways (urea cycle and citric acid cycle) in the cell, we hypothesize that energy dysregulation
results from citric acid cycle disruption and contributes to liver disease in ASLD. We plan to test this hypothesis
by pursuing studies that address the following questions: a) Is there mitochondrial dysfunction in the liver of the
ASL-deficient mice? b) Does citric acid cycle dysfunction contribute to energy dysregulation in hepatocyte-like
cells derived from patients with ASLD?
 Overall, our studies will combine in vivo murine studies and studies in a new in vitro model to investigate the
link between the urea cycle, citric acid cycle and energy dysregulation. Our studies will enable the identification
of potential endpoints for future studies of therapeutic strategies for liver disease in ASLD and possibly other
UCDs. Moreover, the hepatocyte-like cells generated in this proposal will be an important resource for
performing high-throughput screening for therapeutic targets and for dissecting genotype-phenotype
relationships in ASLD. Lastly, on broader terms, these studies have the potential to yield important insights into
the role of energy dysregulation and urea cycle dysfunction in more common forms of liver disease.

## Key facts

- **NIH application ID:** 9899983
- **Project number:** 5R03DK119636-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lindsay C Burrage
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $120,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899983

## Citation

> US National Institutes of Health, RePORTER application 9899983, Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency (5R03DK119636-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899983. Licensed CC0.

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