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.

Hemin-induced suicidal erythrocyte death

“…A wide variety of clinical disorders is known to stimulate eryptosis, including iron deficiency [36], phosphate depletion [6], hemolytic uremic syndrome [43], sepsis [35], malaria [10,37,38], or Wilson's disease [46]. Some of these diseases may cause eryptosis by stimulating the formation of hemin.…”

“…Some of these diseases may cause eryptosis by stimulating the formation of hemin. Furthermore, several eryptosis-triggering xenobiotics and endogeneous substances have been identified, such as cordycepin [50], methylglyoxal [54], amyloid peptides [53], lipopetides [71] retinoic acid [55], paclitaxel [44], amantadine [23], chlorpromazine [1], ciglitazone [58], cyclosporine [56], Bay-5884 [65], curcumin [4], valinomycin [64], listeriolysin [25], aluminum [57], copper [46], bismuth [13], tin [52], cadmium [68], selenium [67], vanadate [27], gold [69], and arsenic [51]. At least in theory, some of those substances may be effective through stimulation of hemin formation.…”

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

“…Ceramide molecules self-associate to small ceramide-enriched membrane microdomains, which have the tendency to spontaneously fuse to large ceramide-enriched membrane domains [36-38]. The formation of ceramide-enriched membrane domains was shown to occur in cells after stimulation via a variety of stimuli including CD95 [39-41], CD40 [42], DR5 [43], FcγRII [44], the PAF-receptor [45], but also after infection with P. aeruginosa [19], Neisseriae gonorrhoeae [46] , Rhinovirus [47], application of stress stimuli such as UV-light [48], cisplatin [49] or Cu 2+ -treatment [50]. The great variety of stimuli that trigger the formation of ceramide-enriched membrane platforms suggests that these membrane domains facilitate signal transduction, but are very likely not part of the specific signal transduction pathway elicited by the these stimuli.…”

“…However, further details of the stimulation of neutral sphingomyelinase are presently not known. The acid sphingomyelinase is activated by oxidation [43, 50, 72]. It is unknown whether the protein is directly oxidized in vivo or regulated via pathways that are redox-sensitive.…”

“…It is unknown whether the protein is directly oxidized in vivo or regulated via pathways that are redox-sensitive. Scavengers of reactive oxygen intermediates prevent activation of the acid sphingomyelinase by stimuli such as DR5 or Cu 2+ [43, 50, 72]. In vitro studies by Qui et al .…”