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Argininosuccinate synthase conditions the response to acute and chronic ethanol‐induced liver injury in mice
Author(s) -
Ming Leung Tung,
Lu Yongke,
Yan Wei,
MorónConcepción José A.,
Ward Stephen C.,
Ge Xiaodong,
Conde de la Rosa Laura,
Nieto Natalia
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25543
Subject(s) - alcoholic liver disease , medicine , endocrinology , liver injury , argininosuccinate synthase , chemistry , nitric oxide synthase , oxidative stress , nitrotyrosine , nitric oxide , citrulline , biochemistry , biology , cirrhosis , arginine , amino acid
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 ( Pgc1 α) 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. (H EPATOLOGY 2012)