Hypoxic conformance of metabolism in primary rat hepatocytes: A model of hepatic hibernation

Authors

  • Ram M. Subramanian,

    Corresponding author
    1. Sections of Gastroenterology and Hepatology & Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL
    • Departments of Gastroenterology and Hepatology, and Pulmonary & Critical Care Medicine, MC 6076, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
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    • fax: 773-702-4736

  • Navdeep Chandel,

    1. Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • G. R. Scott Budinger,

    1. Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Paul T. Schumacker

    1. Division of Neonatology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL
    2. Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
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  • Potential conflict of interest: Nothing to report.

Abstract

Following prolonged hypoxia, mammalian cells invoke adaptive mechanisms to enhance oxygen delivery and promote energy conservation. We previously reported that hepatocytes subjected to prolonged moderate hypoxia (PO2 = 20-50 mmHg for >3 hours) demonstrated a reversible inhibition of cellular respiration with maintenance of cell viability, associated with a decrease in mitochondrial adenosine triphosphate (ATP) synthesis; acute hypoxia (similar PO2 for <30 minutes) did not induce a similar suppression of respiration and ATP synthesis. In the current study, using an in vitro model of primary rat hepatocytes, we measured the changes in metabolic demand for ATP during hypoxic conformance, and tested whether viability is maintained by preferentially suppressing nonessential processes while sustaining processes essential for maintaining cell homeostasis. In addition, the rate of recovery of oxygen consumption and ATP concentrations following reoxygenation after prolonged and acute hypoxia/anoxia was compared. Oxygen consumption and ATP concentrations decreased during prolonged hypoxia compared with acute hypoxia. However, ouabain-inhibitable respiration did not decrease during prolonged hypoxia, indicating that membrane Na+/K+ ATPase activity, an essential process for cell viability, was maintained. In contrast, ATP-dependent glucuronidation and sulfation of acetaminophen, deemed “non-essential” processes, were decreased significantly compared with normoxic cells. After reoxygenation, cells exposed to prolonged moderate hypoxia demonstrated a more rapid recovery of respiration compared to acute hypoxia/anoxia. Conclusion: This “hepatic hibernation” during prolonged moderate hypoxia may represent an anticipatory adaptation that seeks to maintain cell viability while delaying or preventing the onset of lethal hypoxia, and facilitates rapid recovery after the resumption of normoxia. (HEPATOLOGY 2007.)

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