title: Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.
abstract: Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) 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.
authors.affiliation: Institute of Physiology University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Marcus
authors.initials: M
authors.lastname: Schenck
authors.forename: Jan P
authors.initials: JP
authors.lastname: Nicolay
authors.forename: Jan Ulrich
authors.initials: JU
authors.lastname: Becker
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Kempe
authors.forename: Adrian
authors.initials: A
authors.lastname: Lupescu
authors.forename: Saisudha
authors.initials: S
authors.lastname: Koka
authors.forename: Kerstin
authors.initials: K
authors.lastname: Eisele
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Klarl
authors.forename: Herbert
authors.initials: H
authors.lastname: Rübben
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Klaus
authors.initials: K
authors.lastname: Mann
authors.forename: Sibylle
authors.initials: S
authors.lastname: Hildenbrand
authors.forename: Harald
authors.initials: H
authors.lastname: Hefter
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Andreas
authors.initials: A
authors.lastname: Erhardt
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000328:Adult; D000740:Anemia / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D003300:Copper / Q000633:toxicity*; D000073840:Copper-Transporting ATPases; D004912:Erythrocytes / Q000378:metabolism; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects; D006527:Hepatolenticular Degeneration / Q000150:complications / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D008875:Middle Aged; D010718:Phosphatidylserines / Q000378:metabolism; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D002518:Ceramides; D010718:Phosphatidylserines; D003300:Copper; D013108:Sphingomyelin Phosphodiesterase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases