AI Article Synopsis
- Argininosuccinate synthase (ASS) is crucial in regulating protein breakdown, ammonia levels, and nitric oxide production, with its activity linked to liver issues in alcohol consumption.
- Chronic ethanol consumption and binge drinking in mice showed that reduced ASS levels helped prevent liver damage in acute scenarios by lowering nitrosative stress, but led to greater harm in chronic cases due to hyperammonemia and oxidative stress.
- The study concludes that while a partial loss of ASS protects against immediate liver injury, it fails to do so in long-term exposure, where other stress factors like impaired fatty acid oxidation become more significant.
Article Abstract
Unlabelled: 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632528 | PMC |
| http://dx.doi.org/10.1002/hep.25543 | DOI Listing |
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