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Carbamoyl phosphate synthetase-1 is a rapid turnover biomarker in mouse and human acute liver injury.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2014 Aug 01; Vol. 307 (3), pp. G355-64. Date of Electronic Publication: 2014 Jun 12. - Publication Year :
- 2014
-
Abstract
- Several serum markers are used to assess hepatocyte damage, but they have limitations related to etiology specificity and prognostication. Identification of novel hepatocyte-specific biomarkers could provide important prognostic information and better pathogenesis classification. We tested the hypothesis that hepatocyte-selective biomarkers are released after subjecting isolated mouse hepatocytes to Fas-ligand-mediated apoptosis. Proteomic analysis of hepatocyte culture medium identified the mitochondrial matrix protein carbamoyl phosphate synthetase-1 (CPS1) among the most readily detected proteins that are released by apoptotic hepatocytes. CPS1 was also detected in mouse serum upon acute challenge with Fas-ligand or acetaminophen and in hepatocytes upon hypoosmotic stress, independent of hepatocyte caspase activation. Furthermore, CPS1 was observed in sera of mice chronically fed the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mouse CPS1 detectability was similar in serum and plasma, and its half-life was 126 ± 9 min. Immune staining showed that CPS1 localized to mouse hepatocytes but not ductal cells. Analysis of a few serum samples from patients with acute liver failure (ALF) due to acetaminophen, Wilson disease, or ischemia showed readily detectable CPS1 that was not observed in several patients with chronic viral hepatitis or in control donors. Notably, CPS1 rapidly decreased to undetectable levels in sera of patients with acetaminophen-related ALF who ultimately recovered, while alanine aminotransferase levels remained elevated. Therefore, CPS1 becomes readily detectable upon hepatocyte apoptotic and necrotic death in culture or in vivo. Its abundance and short serum half-life, compared with alanine aminotransferase, suggest that it may be a useful prognostic biomarker in human and mouse liver injury.<br /> (Copyright © 2014 the American Physiological Society.)
- Subjects :
- Acetaminophen
Alanine Transaminase blood
Animals
Apoptosis
Biomarkers metabolism
Carbamoyl-Phosphate Synthase (Ammonia) blood
Cells, Cultured
Chemical and Drug Induced Liver Injury blood
Chemical and Drug Induced Liver Injury etiology
Chemical and Drug Induced Liver Injury pathology
Chemical and Drug Induced Liver Injury, Chronic blood
Chemical and Drug Induced Liver Injury, Chronic enzymology
Chemical and Drug Induced Liver Injury, Chronic etiology
Culture Media, Conditioned metabolism
Disease Models, Animal
Fas Ligand Protein metabolism
Half-Life
Hepatitis B, Chronic blood
Hepatitis B, Chronic enzymology
Hepatitis C, Chronic blood
Hepatitis C, Chronic enzymology
Hepatocytes pathology
Humans
Liver pathology
Mice
Necrosis
Prognosis
Pyridines
Time Factors
Carbamoyl-Phosphate Synthase (Ammonia) metabolism
Chemical and Drug Induced Liver Injury enzymology
Hepatocytes enzymology
Liver enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1547
- Volume :
- 307
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 24924744
- Full Text :
- https://doi.org/10.1152/ajpgi.00303.2013