Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury
Open accessAbstract
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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The divergent effects of CPS1 probably reflect its independent roles in creatine metabolism and immune signaling.
“probably reflecting its independent roles in creatine metabolism39 and immune signaling.40”
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CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine
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- Authors
- Park, M.-J., D’Alecy, L. G., Anderson, M. A., Basrur, V., Feng, Y., Brady, G. F., Kim, D.-I., Wu, J., Nesvizhskii, A. I., Lahann, J., Lukacs, N. W., Fontana, R. J., & Omary, M. B.
- Affiliations
- University of Michigan (US)
- Chonnam National University (KR)
- Åbo Akademi University (FI)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-04-12
- Volume
- 116
- Issue
- 18
- Pages
- 9125-9134
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6500125
- OpenAlex
- W2937232990
- Cited by
- 44
- References
- 57
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 2
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Åbo Akademi University Research Portal (submittedVersion)
- Funders
- HHS | National Institutes of Health (R01 DK47918, UL1TR002240, P30 DK34933)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- CPS1, bile, acute liver injury, urea cycle enzymes, extracellular vesicles, hepatic macrophages, anti-inflammatory cytokines, acetaminophen hepatotoxicity
- MeSH terms
- Acetaminophen, Adult, Animals, Bile, Bile Acids and Salts, Carbamoyl-Phosphate Synthase (Ammonia), Female, Humans, Liver, Liver Diseases, Macrophages, Male, Mitochondria, Cytokines, Hepatocytes, Mice, Fas Ligand Protein, Acute Lung Injury
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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