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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 Feb; 18(1):38-47.HP

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 regulating 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 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition 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 β 1 (TGFβ1), 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, TGFβ1, 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, TGFβ1, 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 TGFβ1 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.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Ontario, Canada; Division of Cardiac Surgery, Department of Surgery, University of Toronto, Ontario, Canada.Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Cell Physiology, Department of the Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. Electronic address: lixinliu6@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30243878

Citation

Ren, Jun-Jie, et al. "Insulin-like Growth Factor Binding Protein Related Protein 1 Knockdown Attenuates Hepatic Fibrosis Via the Regulation of MMPs/TIMPs in Mice." Hepatobiliary & Pancreatic Diseases International : HBPD INT, vol. 18, no. 1, 2019, pp. 38-47.
Ren JJ, Huang TJ, Zhang QQ, et al. Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. HBPD INT. 2019;18(1):38-47.
Ren, J. J., Huang, T. J., Zhang, Q. Q., Zhang, H. Y., Guo, X. H., Fan, H. Q., Li, R. K., & Liu, L. X. (2019). Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. Hepatobiliary & Pancreatic Diseases International : HBPD INT, 18(1), 38-47. https://doi.org/10.1016/j.hbpd.2018.08.008
Ren JJ, et al. Insulin-like Growth Factor Binding Protein Related Protein 1 Knockdown Attenuates Hepatic Fibrosis Via the Regulation of MMPs/TIMPs in Mice. HBPD INT. 2019;18(1):38-47. PubMed PMID: 30243878.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. AU - Ren,Jun-Jie, AU - Huang,Ting-Juan, AU - Zhang,Qian-Qian, AU - Zhang,Hai-Yan, AU - Guo,Xiao-Hong, AU - Fan,Hui-Qin, AU - Li,Ren-Ke, AU - Liu,Li-Xin, Y1 - 2018/08/29/ PY - 2018/04/21/received PY - 2018/07/30/accepted PY - 2018/9/24/pubmed PY - 2019/5/30/medline PY - 2018/9/24/entrez KW - Hedgehog signaling pathway KW - Hepatic fibrosis KW - Insulin-like growth factor binding protein related protein 1 KW - Matrix metalloproteinase KW - Tissue inhibitor of metalloproteinase KW - Ultrasound-targeted microbubble destruction SP - 38 EP - 47 JF - Hepatobiliary & pancreatic diseases international : HBPD INT JO - HBPD INT VL - 18 IS - 1 N2 - 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 regulating 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 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition 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 β 1 (TGFβ1), 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, TGFβ1, 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, TGFβ1, 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 TGFβ1 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. SN - 1499-3872 UR - https://www.unboundmedicine.com/medline/citation/30243878/Insulin_like_growth_factor_binding_protein_related_protein_1_knockdown_attenuates_hepatic_fibrosis_via_the_regulation_of_MMPs/TIMPs_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1499-3872(18)30189-9 DB - PRIME DP - Unbound Medicine ER -