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Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

ABSTRACT: 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 (pAMPK?) to total AMPK? ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1? (Pgc1?) messenger RNAs (mRNAs), lower fatty acid ?-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.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 ?-oxidation are key events.

SUBMITTER: Leung TM

PROVIDER: S-EPMC4632528 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

Leung Tung Ming TM Lu Yongke Y Yan Wei W Morón-Concepción Jose A JA Ward Stephen C SC Ge Xiaodong X Conde de la Rosa Laura L Nieto Natalia N

Hepatology (Baltimore, Md.) 20120501 5

<h4>Unlabelled</h4>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 c ...[more]

PMID: 22213272

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Dataset Information

Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

Publications

Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

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