ArticleProceedings of the National Academy of Sciences of the United States of America2019
Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 45 citations in OpenAlex.
- CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine.Gut · 2026Review
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- The Role and Treatment Strategies of Ammonia-Related Metabolism in Tumor Microenvironment.Current gene therapy · 2025Review
- Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients.International journal of molecular sciences · 2024Article
- Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Associations between Chronic Kidney Disease and Migraine Incidence: Findings from a Korean Longitudinal Big Data Study.Journal of personalized medicine · 2024Article
- The Role of Carbamoyl Phosphate Synthetase 1 as a Prognostic Biomarker in Patients With Acetaminophen-induced Acute Liver Failure.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2023Article
- Hypoosmosis alters hepatocyte mitochondrial morphology and induces selective release of carbamoyl phosphate synthetase 1.American journal of physiology. Gastrointestinal and liver physiology · 2023Article
- Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.Cell genomics · 2023Article
- Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans.Nature communications · 2023Article
- Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform.Journal of thrombosis and haemostasis : JTH · 2023Article
- Identification and Characterization of Elevated Expression of Transferrin and Its Receptor TfR1 in Mouse Models of Depression.Brain sciences · 2022Article
- Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.Antioxidants & redox signaling · 2022Review
- Genetic Variation in the Mitochondrial Glycerol-3-Phosphate Acyltransferase Is Associated With Liver Injury.Hepatology (Baltimore, Md.) · 2021Article
- Plasmodium sporozoite phospholipid scramblase interacts with mammalian carbamoyl-phosphate synthetase 1 to infect hepatocytes.Nature communications · 2021Article
- Deciphering the Dynamic Complexities of the Liver Microenvironment - Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI).The AAPS journal · 2021Review
- Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma.Cancers · 2021Article
- Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury.Frontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.