Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9125-9134. doi: 10.1073/pnas.1822173116. Epub 2019 Apr 12.
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.
氨甲酰磷酸合成酶 1（CPS1）是肝细胞中主要的线粒体尿素循环酶。在急性肝损伤期间，它会被释放到小鼠和人血液中，并且其半衰期很短。CPS1 在血液中的功能及其在血清中半衰期短的原因尚不清楚。我们表明 CPS1 正常释放到小鼠和人胆汁中，并且在急性肝损伤期间病理性地释放到血液中。其他细胞质和线粒体尿素循环酶也存在于正常小鼠胆汁中。血清、胆汁和纯化的 CPS1 表现出与细胞外囊泡重叠的沉淀特性，这是由于 CPS1 尽管主要作为可溶性蛋白释放，但仍具有聚集的倾向。在肝损伤期间，血液中的 CPS1 被单核细胞迅速隔离，导致单核细胞 M2 极化并独立于其酶活性归巢到肝脏。重组 CPS1（rCPS1），但不是对照 r-转铁蛋白，增加了肝巨噬细胞的数量和吞噬活性。值得注意的是，rCPS1 不会直接激活肝巨噬细胞；相反，它激活骨髓和循环单核细胞，然后归巢到肝脏。rCPS1 给药可预防 Fas 配体或对乙酰氨基酚诱导的小鼠肝损伤，但在巨噬细胞缺陷小鼠中这种保护作用不存在。此外，即使在损伤诱导后进行治疗性 rCPS1 给药，也可以保护免受对乙酰氨基酚诱导的肝损伤。总之，CPS1 通常存在于胆汁中，但在肝损伤时会被肝细胞释放到血液中。我们证明了 CPS1 在急性肝损伤期间作为抗炎保护细胞因子的非酶功能。
