Insulin- like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice
Jun-Jie Ren a , Ting-Juan Huang a , Qian-Qian Zhang a , b , c , Hai-Yan Zhang a , b , c , Xiao-Hong Guo a , b , c , Hui-Qin Fan a , b , c , Ren-Ke Li d , e , Li-Xin Liu a , b , c , ∗
a Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030 0 01, China
b Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030 0 01, China
c Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030 0 01, China
d Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Ontario, Canada
e Division of Cardiac Surgery, Department of Surgery, University of Toronto, Ontario, Canada
∗ Corresponding author at: Department of Gastroenterology and Hepatology and Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
E-mail address: lixinliu6@hotmail.com (L.-X. Liu).
Abstract：Background: Previous research suggested that insulin-like growth factor binding protein related protein 1 (IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) play an essential role in hepatic fibrogenesis by regu- lating homeostasis and remodeling of the extracellular matrix (ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis.
Methods: Hepatic fibrosis was induced by thioacetamide (TAA) in mice. Knockdown of IGFBPrP1 expres- sion by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhi- bition of the Hedgehog (Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin ( α-SMA), transforming growth factor β1 (TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog (Shh), and glioblastoma family transcription factors (Gli1) were investigated by immunohistochemical staining and Western blotting analysis.
Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance.
Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.
. [J]. Hepatobiliary Pancreat Dis Int, 2019, 18(1): 38-47.
Ren JJ, Huang TJ, Zhang QQ, Zhang HY, Guo XH, Fan HQ, Li RK, Liu LX. Insulin- like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. Hepatobiliary Pancreat Dis Int, 2019, 18(1): 38-47.
2019, Vol. 18 
