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Int J Clin Exp Pathol 2011;4(5):513-520

Original Article
Down-regulation of tTG expression by RNAi inhibits HSC proliferation and attenuates
liver fibrosis

Gang Zhao, Zhi-Qi Zhang, Bin Zhang, Meng Luo,Yong-Wei Sun, Zhi-Yong Wu

Department of General Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

Received May 24, 2011; accepted June 10, 2011; Epub June 12, 2011; published June 20, 2011

Abstract: Purpose: Expressed in hepatic stellate cell (HSC), tTG is involved in fibrotic diseases including human hepatic fibrosis by promoting
the cross-linking of ECM and participating in the initiation and/or progression of liver fibrosis. The purpose of this study is to identify whether
depletion of tTG could attenuate liver fibrosis. Methods: In this study, primary hepatic stellate cells were isolated, purified, and cultured from rat.
Expression of tTG gene was downregulated by lentivirus-mediated RNAi, and the effects on the activation, proliferation and apoptosis of HSC
were investigated both in vitro and in vivo. Results: Lentivirus-mediated RNAi successfully reduced the endogenous expression of tTG in
cultured cells. The down-regulation of tTG markedly inhibited the proliferation of HSC and attenuated the synthesis of Collagen-1. The
downregulation of tTG also markedly reduced the level of tTG and hydroxyproline induced by CCl4 in rat livers at week 8 and week 12 after
injection of CCl4. Conclusions: In summary, tTG plays an important role in liver fibrosis. Lentivirus-mediated downregulation of tTG showed a
potential anti-fibrosis effect in rats, providing new evidence that the involvement of tTG in HSC activation, also suggesting that RNAi-directed
targeting of tTG may be used as a potent and specific therapeutic tool for the treatment of liver fibrosis, especially in inhibiting the activation of
HSC. (IJCEP1105006)

Keywords: Tissue transglutaminase, RNAi, hepatic stellate cells, liver fibrosis, lentiviral vector

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Address all correspondence to:
Zhi-yong Wu, MD
Department of General Surgery, Renji Hospital
No. 1630 Dongfang Road
Shanghai, China.