Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide

Speaker: 陳美君                                                    Time: 15:10~16:00, Apr.18, 2007

Commentator: 林秋烽 老師                                         Place: Room 601

Abstract:

Wilson disease is an autosomal recessive genetic disorder caused by mutation of the copper-transporting gene ATP7B which participates in excluding the Cu²⁺ into the bile. Excessive Cu²⁺ in cells leads to the formation of reactive oxygen species (ROS) and cell death resulting in symptoms such as progressive hepatic cirrhosis, neurological disorders, and anemia. Acid sphingomyelinase (Asm) activity is increased under cellular stress conditions like UV light, g-irradiation and death receptor, leading to ceramide accumulation and apoptosis. In this study, the authors investigated the role of Asm- and ceramide-mediated cell death in Cu²⁺-triggered liver damage and anemia. Mouse hepatocytes treated with Cu²⁺ underwent apoptosis via the induction of ROS, Asm activation, and ceramide formation. Using genetic, drug, or siRNA inhibition of Asm prevented Cu²⁺- induced HepG2, normal, and Atp7b^-/- mouse hepatocytes from death. In addition, Cu²⁺ induced the activation of Asm and phosphatidylserine exposure on erythrocytes, this contributed to erythrocyte clearance from the blood, as evidenced by anemia occurring in Wilson disease. Besides, blood samples from patients revealed an increased Asm activity, ceramide and phosphatidylserine exposure on erythrocytes, indicating a parallel between experimental models and human disease. Furthermore, daily treatment of Atp7b-deficient LEC rats with Asm inhibitor could prevent the accumulation of ceramide in liver cells and the development of liver fibrosis and apoptosis, leading to an increased survival. These data establish the role of Asm and ceramide in Cu²⁺- induced apoptosis, providing new therapeutic measure for Wilson disease.

References:

1.          Lang, P. A. et al. 2007. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat. Med. 13: 164-170.

2.          Seth, R. et al. 2004. In vitro assessment of copper-induced toxicity in the human hepatoma line, HepG2. Toxicol. In Vitro 18: 501-509.

3.          Petrache, I. et al. 2005. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat. Med. 11: 491-498.