Article abstract
Nature Medicine 13, 164 - 170 (2007)
Published online: 28 January 2007 | doi:10.1038/nm1539
Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide
Philipp A Lang1, Marcus Schenck2,3, Jan P Nicolay1, Jan Ulrich Becker4, Daniela S Kempe1, Adrian Lupescu1, Saisudha Koka1, Kerstin Eisele1, Barbara A Klarl1, Herbert Rübben3, Kurt W Schmid4, Klaus Mann5, Sibylle Hildenbrand6, Harald Hefter7, Stephan M Huber1, Thomas Wieder1,9, Andreas Erhardt8, Dieter Häussinger8, Erich Gulbins2,10 & Florian Lang1,10
Abstract
Wilson disease is caused by accumulation of Cu2+ in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu2+ triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu2+-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu2+ induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.
- Institute of Physiology University of Tübingen, 72076 Tübingen, Germany.
- Institute of Molecular Biology, University of Duisburg-Essen, 45122 Essen, Germany.
- Department of Urology, University of Duisburg-Essen, 45122 Essen, Germany.
- Institute of Pathology and Neuropathology, University of Duisburg-Essen, 45122 Essen, Germany.
- Department of Internal Medicine, University Clinic, University of Duisburg-Essen, 45122 Essen, Germany.
- Department of Occupational and Social Medicine, University of Tübingen, 72076 Tübingen, Germany.
- Department of Neurology, University of Düsseldorf, 40225 Düsseldorf, Germany.
- Department of Gastroenterology, Hepatology and Infectiology, University of Düsseldorf, 40225 Düsseldorf, Germany.
- Present address: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
- These authors contributed equally to this work.
Correspondence to: Florian Lang1,10 e-mail: florian.lang@uni-tuebingen.de
Correspondence to: Erich Gulbins2,10 e-mail: erich.gulbins@uni-due.de
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