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University of Michigan Medical School

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Proc. Natl. Acad. Sci. USA, First published April 12, 2019 | https://doi.org/10.1073/pnas.1822173116 Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury

Min-Jung Park^a,1, Louis G. D’Alecy^a, Michelle A. Anderson^b, Venkatesha Basrur^c, Yongjia Feng^a, Graham F. Brady^a,b, Dong-il Kim^d, Jun Wu^a,e, Alexey I. Nesvizhskii^c, Joerg Lahann^f,g, Nicholas W. Lukacs^c, Robert J. Fontana^b, and M. Bishr Omary^a,b,h,1

^a Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; ^b Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109;^c Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; ^d Department of Physiology, College of Veterinary Medicine, Chonnam National University, 61186 Gwangju, Republic of Korea; ^eLife Sciences Institute, University of Michigan, Ann Arbor, MI 48109; ^f Biointerfaces Institute, College of Engineering, University of Michigan, Ann Arbor, MI 48109; ^g Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109; and ^h Cell Biology, Faculty of Science and Technology, Åbo Akademi University, 20500 Turku, Finland

¹To whom correspondence may be addressed.

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.

mitochondria, bile proteome, macrophage polarization, acetaminophen, Fas ligand

논문정보

형식Research article
게재일2019년 04월 (BRIC 등록일 2019-04-24)
연구진국내+국외 연구진
분야 생명과학 > 생리학

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