scholarly journals Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury

2019 ◽  
Vol 116 (18) ◽  
pp. 9125-9134 ◽  
Author(s):  
Min-Jung Park ◽  
Louis G. D’Alecy ◽  
Michelle A. Anderson ◽  
Venkatesha Basrur ◽  
Yongjia Feng ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Damage ◽  
Half Life ◽  
Fas Ligand ◽  
Urea Cycle ◽  
Acute Liver Injury ◽  
Carbamoyl Phosphate ◽  
Human Bile ◽  
Cycle Enzyme ◽  
Short Half Life

Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life. The function of CPS1 in blood and the reason for its short half-life in serum are unknown. We show that CPS1 is released normally into mouse and human bile, and pathologically into blood during acute liver injury. Other cytoplasmic and mitochondrial urea cycle enzymes are also found in normal mouse bile. Serum, bile, and purified CPS1 manifest sedimentation properties that overlap with extracellular vesicles, due to the propensity of CPS1 to aggregate despite being released primarily as a soluble protein. During liver injury, CPS1 in blood is rapidly sequestered by monocytes, leading to monocyte M2-polarization and homing to the liver independent of its enzyme activity. Recombinant CPS1 (rCPS1), but not control r-transferrin, increases hepatic macrophage numbers and phagocytic activity. Notably, rCPS1 does not activate hepatic macrophages directly; rather, it activates bone marrow and circulating monocytes that then home to the liver. rCPS1 administration prevents mouse liver damage induced by Fas ligand or acetaminophen, but this protection is absent in macrophage-deficient mice. Moreover, rCPS1 protects from acetaminophen-induced liver injury even when given therapeutically after injury induction. In summary, CPS1 is normally found in bile but is released by hepatocytes into blood upon liver damage. We demonstrate a nonenzymatic function of CPS1 as an antiinflammatory protective cytokine during acute liver injury.

scholarly journals Carbamoyl phosphate synthetase-1 is a rapid turnover biomarker in mouse and human acute liver injury

2014 ◽  
Vol 307 (3) ◽  
pp. G355-G364 ◽  
Author(s):  
Sujith V. W. Weerasinghe ◽  
You-Jin Jang ◽  
Robert J. Fontana ◽  
M. Bishr Omary
Keyword(s):  
Liver Injury ◽  
Alanine Aminotransferase ◽  
Half Life ◽  
Fas Ligand ◽  
Mouse Serum ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Ductal Cells ◽  
Mouse Hepatocytes ◽  
Carbamoyl Phosphate Synthetase 1

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.

scholarly journals Mice deficient in the urea-cycle enzyme, carbamoyl phosphate synthetase i, die during the early neonatal period from hyperammonemia

Hepatology ◽  
1999 ◽  
Vol 29 (1) ◽  
pp. 181-185 ◽  
Author(s):  
J. Paul Schofield ◽  
J. Paul Schofield ◽  
Timothy M. Cox ◽  
C. Thomas Caskey ◽  
Maki Wakamiya
Keyword(s):  
Urea Cycle ◽  
Neonatal Period ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Cycle Enzyme ◽  
Early Neonatal Period ◽  
Urea Cycle Enzyme

Indoline derivatives mitigate liver damage in a mouse model of acute liver injury

2017 ◽  
Vol 69 (5) ◽  
pp. 894-902 ◽  
Author(s):  
Efrat Finkin-Groner ◽  
Shlomi Finkin ◽  
Shani Zeeli ◽  
Marta Weinstock
Keyword(s):  
Liver Injury ◽  
Mouse Model ◽  
Liver Damage ◽  
Acute Liver Injury

scholarly journals Caspase-1-Independent, Fas/Fas Ligand–Mediated IL-18 Secretion from Macrophages Causes Acute Liver Injury in Mice

Immunity ◽  
1999 ◽  
Vol 11 (3) ◽  
pp. 359-367 ◽  
Author(s):  
Hiroko Tsutsui ◽  
Nobuhiko Kayagaki ◽  
Keisuke Kuida ◽  
Hiroki Nakano ◽  
Nobuki Hayashi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fas Ligand ◽  
Acute Liver Injury ◽  
Caspase 1

scholarly journals Histone methyltransferase G9a protects against acute liver injury through GSTP1

2019 ◽  
Vol 27 (4) ◽  
pp. 1243-1258 ◽  
Author(s):  
Yu Zhang ◽  
Weili Xue ◽  
Wenquan Zhang ◽  
Yangmian Yuan ◽  
Xiuqin Zhu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Damage ◽  
Acute Liver Injury ◽  
Epigenetic Modification ◽  
Histone Methyltransferase ◽  
Methyltransferase Activity ◽  
Detoxifying Enzymes ◽  
Apap Overdose ◽  
Deficient Mice

Abstract Acute liver injury is commonly caused by bacterial endotoxin/lipopolysaccharide (LPS), and by drug overdose such as acetaminophen (APAP). The exact role of epigenetic modification in acute liver injury remains elusive. Here, we investigated the role of histone methyltransferase G9a in LPS- or APAP overdose-induced acute liver injury. Under d-galactosamine sensitization, liver-specific G9a-deficient mice (L-G9a−/−) exhibited 100% mortality after LPS injection, while the control and L-G9a+/− littermates showed very mild mortality. Moreover, abrogation of hepatic G9a or inhibiting the methyltransferase activity of G9a aggravated LPS-induced liver damage. Similarly, under sublethal APAP overdose, L-G9a−/− mice displayed more severe liver injury. Mechanistically, ablation of G9a inhibited H3K9me1 levels at the promoters of Gstp1/2, two liver detoxifying enzymes, and consequently suppressed their transcription. Notably, treating L-G9a−/− mice with recombinant mouse GSTP1 reversed the LPS- or APAP overdose-induced liver damage. Taken together, we identify a novel beneficial role of G9a-GSTP1 axis in protecting against acute liver injury.

Glucagon Receptor Inhibition Reduces Hyperammonemia and Lethality in Male Mice with Urea Cycle Disorder

Endocrinology ◽  
2020 ◽  
Vol 162 (1) ◽  
Author(s):  
Katie Cavino ◽  
Biin Sung ◽  
Qi Su ◽  
Erqian Na ◽  
Jinrang Kim ◽  
...  
Keyword(s):  
Liver Injury ◽  
Urea Cycle ◽  
Critical Role ◽  
Clinical Manifestations ◽  
High Protein Diet ◽  
Glucagon Receptor ◽  
Blocking Antibody ◽  
Receptor Blocking ◽  
Cycle Enzyme ◽  
Receptor Inhibition

Abstract The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury, or failure and glutamine synthetase (GS) deficiency result in hyperammonemia, serious clinical conditions, and lethality. In this study we used a mouse model with a defect in the urea cycle enzyme ornithine transcarbamylase (Otcspf-ash) to test the hypothesis that glucagon receptor inhibition using a monoclonal blocking antibody will reduce the hyperammonemia and associated lethality induced by a high-protein diet, which exacerbates disease. We found reduced expression of glutaminase, which degrades glutamine and increased expression of GS in livers of Otcspf-ash mice treated with the glucagon receptor blocking antibody. The gene expression changes favor ammonia consumption and were accompanied by increased circulating glutamine levels and diminished hyperammonemia. Otcspf-ash mice treated with the glucagon receptor-blocking antibody gained lean and body mass and had increased survival. These data suggest that glucagon receptor inhibition using a monoclonal antibody could reduce the risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury, or failure and GS deficiency.

scholarly journals Acute liver injury following acetaminophen administration does not activate atrophic pathways in the mouse diaphragm

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
C. S. Bruells ◽  
P. Duschner ◽  
G. Marx ◽  
G. Gayan-Ramirez ◽  
N. Frank ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Liver Injury ◽  
Liver Damage ◽  
Acute Liver Injury ◽  
Serum Levels ◽  
Acute Liver Damage ◽  
Markers Of Inflammation ◽  
Amino Phenol ◽  
And Oxidative Stress

AbstractN-acetyl-para-amino phenol (APAP, usually named paracetamol), which is commonly used for its analgesic and antipyretic properties may lead to hepatotoxicity and acute liver damage in case of overdoses. Released cytokines and oxidative stress following acute liver damage may affect other organs’ function notably the diaphragm, which is particularly sensitive to oxidative stress and circulating cytokines. We addressed this issue in a mouse model of acute liver injury induced by administration of APAP. C57BL/6J mice (each n = 8) were treated with N-acetyl-para-amino phenol (APAP) to induce acute drug caused liver injury and sacrificed 12 or 24 h afterwards. An untreated group served as controls. Key markers of inflammation, proteolysis, autophagy and oxidative stress were measured in diaphragm samples. In APAP treated animals, liver damage was proven by the enhanced serum levels of alanine aminotransferase and aspartate aminotransferase. In the diaphragm, besides a significant increase in IL 6 and lipid peroxidation, no changes were observed in key markers of the proteolytic, and autophagy signaling pathways, other inflammatory markers and fiber dimensions. The first 24 h of acute liver damage did not impair diaphragm atrophic pathways although it slightly enhanced IL-6 and lipid peroxidation. Whether longer exposure might affect the diaphragm needs to be addressed in future experiments.

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