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Vol. 19, Issue 10, 4238-4248, October 2008

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Nuclear Cathepsin F Regulates Activation Markers in Rat Hepatic Stellate Cells

Department of Tissue Engineering, Institute of Bioengineering and Nanotechnology, Singapore 138669

Submitted March 18, 2008; Revised July 14, 2008; Accepted July 23, 2008
Monitoring Editor: William P. Tansey

Activation of hepatic stellate cells during liver fibrosis is a major event facilitating an increase in extracellular matrix deposition. The up-regulation of smooth muscle -actin and collagen type I is indicative of the activation process. The involvement of cysteine cathepsins, a class of lysosomal cysteine proteases, has not been studied in conjunction with the activation process of hepatic stellate cells. Here we report a nuclear cysteine protease activity partially attributed to cathepsin F, which co-localizes with nuclear speckles. This activity can be regulated by treatment with retinol/palmitic acid, known to reduce the hepatic stellate cell activation. The treatment for 48 h leads to a decrease in activity, which is coupled to an increase in cystatin B and C transcripts. Cystatin B knockdown experiments during the same treatment confirm the regulation of the nuclear activity by cystatin B. We demonstrate further that the inhibition of the nuclear activity by E-64d, a cysteine protease inhibitor, results in a differential regulation of smooth muscle -actin and collagen type I transcripts. On the other hand, cathepsin F small interfering RNA transfection leads to a decrease in nuclear activity and a transcriptional down-regulation of both activation markers. These findings indicate a possible link between nuclear cathepsin F activity and the transcriptional regulation of hepatic stellate cell activation markers.

Address correspondence to: Gunter Maubach (gmaubach{at}ibn.a-star.edu.sg) or Lang Zhuo (lzhuo{at}ibn.a-star.edu.sg)

Abbreviations used: CMK, chloromethyl ketone; DTT, dithiothreitol; GFAP, glial fibrillary acidic protein; HSC, hepatic stellate cell; IF, immunofluorescence; LHVS, N-morpholinurea-leucine-homophenyl alanine-vinylsulfone-phenyl; MCA, 4-methylcoumaryl-7-amide; PDI, protein disulfide isomerase; PFA, paraformaldehyde; RAR, retinoic acid receptor; SMAA, smooth muscle -actin; TESS, transcription element search software.