Cathepsin B overexpression in Niemann-Pick disease

Niemann Pick disease (NPD) is a lysosomal storage disease caused by the loss of acid sphingomyelinase (ASMase) that features neurodegeneration and liver disease. Since ASMase knockout mice models NPD and our previous findings revealed that ASMase activates cathepsins B/D (CtsB/D), our aim was to investigate the expression and processing of CtsB/D in hepatic stellate cells (HSC) from ASMase null mice and their role in liver fibrosis. Surprisingly, HSC from ASMase knockout mice exhibit increased basal level and activity of CtsB as well as its in vitro processing in culture, paralleling the enhanced expression of fibrogenic markers α-SMA (alpha-smooth muscle actin), TGF-β and Col1A1 (procollagen-α1(I)). Moreover, pharmacological inhibition of CtsB blunted the expression of αSMA, Col1A1 and proliferation of HSC cells from ASMase knockout mice. Consistent with the enhanced activation of CtsB in HSC from ASMase null mice, the in vivo liver fibrosis induced by chronic treatment with CCl4 increased in ASMase null compared to wildtype mice, an effect that was reduced upon CtsB inhibition. In addition to liver, the enhanced proteolytic processing of CtsB was also observed in brain and lung of ASMase knockout mice, suggesting that the overexpression of CtsB may underlie the phenotype of NPD. Thus, these findings reveal a functional relationship between ASMase and CtsB and that the ablation of ASMase leads to the enhanced processing and activation of CtsB. Therefore, targeting CtsB may be of relevance in the treatment of liver fibrosis in patients with NPD. Acid sphingomyelinase (ASMase; EC 3.2.1.14) is a member of an enzyme family that catalyzes the breakdown of sphingomyelin into ceramide. ASMase works optimally at acidic pH and is mainly located in the endo/lysosomal compartments (1). Besides its important participation as key structural component of biological membranes, ceramide is recognized as a critical second messenger, which regulates many cell functions (2,3). In particular, ceramide generation by ASMase is rapid and transient and plays a proapoptotic role in response to many different stimuli (2,3). ASMase derives from a http://www.jbc.org/cgi/doi/10.1074/jbc.M111.272393 The latest version is at JBC Papers in Press. Published on November 18, 2011 as Manuscript M111.272393