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Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential
Author(s) -
Moles Anna,
Tarrats Núria,
FernándezCheca José C.,
Marí Montserrat
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22753
Subject(s) - hepatic stellate cell , microbiology and biotechnology , cathepsin , cathepsin b , cancer research , cell growth , protein kinase b , biology , transdifferentiation , growth factor , chemistry , signal transduction , stem cell , endocrinology , biochemistry , receptor , enzyme
Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of α‐smooth muscle actin and transforming growth factor‐β during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreased HSC proliferation and the expression of phenotypic markers of HSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet‐derived growth factor. Moreover, during in vivo liver fibrogenesis caused by CCl 4 administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl 4 ‐induced inflammation, HSC activation, and collagen deposition. Conclusion: These findings support a critical role for cathepsins in HSC activation, suggesting that the antagonism of cathepsins in HSCs may be of relevance for the treatment of liver fibrosis. (H EPATOLOGY 2009.)