*These authors contributed equally to this work.
Article first published online: 19 APR 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 5, pages 1596–1609, May 2012
How to Cite
Ming Leung, T., Lu, Y., Yan, W., Morón-Concepción, J. A., Ward, S. C., Ge, X., Conde de la Rosa, L. and Nieto, N. (2012), Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice. Hepatology, 55: 1596–1609. doi: 10.1002/hep.25543
Potential conflict of interest: Nothing to report.
Grant support: US Public Health service grants 5R01 AA017733, 5R01 AA017733-01S1, 5P20 AA017067, 5P20 AA017067-01S1 and 5P20 AA017067-03S1 from the National Institute on Alcohol Abuse and Alcoholism (to N.N.).
- Issue published online: 19 APR 2012
- Article first published online: 19 APR 2012
- Accepted manuscript online: 24 DEC 2011 02:07AM EST
- Manuscript Accepted: 22 NOV 2011
- Manuscript Received: 23 JUL 2011
Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels, and NO· generation. Because a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as coinduced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhosis patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. To investigate the contribution of ASS to the pathophysiology of ALD, wildtype (WT) and Ass+/− mice (Ass−/− are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Compared with WT, Ass+/− mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction, and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress by way of the L-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol-treated Ass+/− mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase alpha (pAMPKα) to total AMPKα ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) messenger RNAs (mRNAs), lower fatty acid β-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense, and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. Conclusion: Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid β-oxidation are key events. (HEPATOLOGY 2012)