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Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease.
- Source :
-
Journal of hepatology [J Hepatol] 2015 Dec; Vol. 63 (6), pp. 1421-8. Date of Electronic Publication: 2015 Aug 08. - Publication Year :
- 2015
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Abstract
- Background & Aims: Ubiquitination is a reversible protein modification involved in the major cellular processes that define cell phenotype and behaviour. Ubiquitin modifications are removed by a large family of proteases named deubiquitinases. The role of deubiquitinases in hepatic stellate cell (HSC) activation and their contribution to fibrogenesis are poorly defined. We have identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, determined its function in activated HSC and its potential as a therapeutic target for fibrosis.<br />Methods: Deubiquitinase expression was determined in day 0 and day 10 HSC. Increased UCHL1 expression was confirmed in human HSC and in an alcoholic liver disease (ALD) patient liver. The importance of UCHL1 in hepatic fibrosis was investigated in CCl4 and bile duct ligation injured mice using a pharmacological inhibitor (LDN 57444). The effects of UCHL1 inhibition on HSC proliferation were confirmed by Western blot and 3H thymidine incorporation.<br />Results: Here we report that pharmacological inhibition of UCHL1 blocks progression of established fibrosis in CCl4 injured mice. UCHL1 siRNA knockdown, LDN 57444 treatment, or HSC isolated from UCHL1(-/-) mice show attenuated proliferation in response to the mitogen, platelet-derived growth factor. Additionally, we observed changes in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb) in the absence of UCHL1 highlighting a potential mechanism for the reduced proliferative response.<br />Conclusions: UCHL1 expression is highly upregulated upon HSC activation and is involved in the regulation of HSC proliferation. This study highlights therapeutic opportunities for pharmacological targeting of UCHL1 in chronic liver disease.<br /> (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Biomarkers metabolism
Carbon Tetrachloride toxicity
Cell Proliferation
Cell Transdifferentiation
Cells, Cultured
Chronic Disease
Gene Knockdown Techniques
Hepatic Stellate Cells enzymology
Hepatic Stellate Cells pathology
Humans
Liver Cirrhosis, Experimental enzymology
Liver Cirrhosis, Experimental pathology
Liver Diseases pathology
Liver Diseases therapy
Liver Diseases, Alcoholic enzymology
Liver Diseases, Alcoholic pathology
Mice
Mice, Knockout
Myofibroblasts enzymology
Myofibroblasts pathology
RNA, Messenger genetics
RNA, Messenger metabolism
Rats
Ubiquitin Thiolesterase antagonists & inhibitors
Ubiquitin Thiolesterase deficiency
Ubiquitin Thiolesterase genetics
Ubiquitin-Specific Proteases genetics
Ubiquitin-Specific Proteases metabolism
Ubiquitination
Liver Diseases enzymology
Ubiquitin Thiolesterase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 63
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 26264933
- Full Text :
- https://doi.org/10.1016/j.jhep.2015.07.034