Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 2, Pages 1178-1188Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.272393
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Funding
- Research Center for Liver and Pancreatic Diseases, National Institute on Alcohol Abuse and Alcoholism [P50-AA-11999]
- Instituto de Salud Carlos III [PI10/02114]
- Plan Nacional de I+D, Spain [2009-11417]
- Fundacio La Marato de TV3
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Niemann-Pick disease (NPD) is a lysosomal storage disease caused by the loss of acid sphingomyelinase (ASMase) that features neurodegeneration and liver disease. Because ASMase-knock-out 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 (HSCs) from ASMase-null mice and their role in liver fibrosis. Surprisingly, HSCs from ASMase-knock-out 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 alpha-smooth muscle actin (alpha-SMA), TGF-beta, and pro-collagen alpha 1(I) (Col1A1). Moreover, pharmacological inhibition of CtsB blunted the expression of alpha-SMA and Col1A1 and proliferation of HSCs from ASMase-knock-out mice. Consistent with the enhanced activation of CtsB in HSCs from ASMase-null mice, the in vivo liver fibrosis induced by chronic treatment with CCl4 increased in ASMase-null compared with wild-type 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-knock-out 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.
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