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



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.
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA.
Tung Ming
TM
Leung
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA.
Yongke
Y
Lu
Institute for Systems Biology, 1441 North 34 Street, Seattle, WA 98103, USA.
Wei
W
Yan
Department of Anesthesiology, Columbia University Medical Center, 630 West 168 Street, New York, NY 10032, USA.
Jose A
JA
Morón-Concepción
Department of Pathology, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY 10029, USA.
Stephen C
SC
Ward
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA.
Xiaodong
X
Ge
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA.
Laura
L
Conde de la Rosa
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA.
Natalia
N
Nieto
D000208:Acute Disease; D000428:Alcohol Drinking / Q000378:metabolism*; D000437:Alcoholism / Q000201:enzymology*; D000818:Animals; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol; D005260:Female; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D009569:Nitric Oxide; C002744:3-nitrotyrosine; D000431:Ethanol; D014443:Tyrosine; D019392:Cytochrome P-450 CYP2E1; D001124:Argininosuccinate Synthase