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IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling.
World J Gastroenterol. 2014 Jun 07; 20(21):6523-33.WJ

Abstract

AIM

To investigate the role and mechanism of insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) in the development of liver fibrosis.

METHODS

An in vitro model using hepatic stellate cell (HSC)-T6 cells and an in vivo model of rat liver overexpressing IGFBPrP1 were established using an IGFBPrP1-expressing recombinant adenovirus. The expression of IGFBPrP1 was examined by immunofluorescence, and the expression of collagen I and fibronectin was measured by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The expression of Smad2/3 and p-Smad2/3 was examined by Western blot and immunohistochemistry. A shSmad3-expressing recombinant adenovirus (AdshSmad3) was designed and used to knockdown the Smad3 gene in HSC-T6 cells and rat liver fibrosis transfected with IGFBPrP1. The expression of collagen I, fibronectin, and α-smooth muscle actin (α-SMA) was determined by Western blot analysis and immunohistochemistry. Hepatocyte apoptosis was assessed using TUNEL assay.

RESULTS

IGFBPrP1 overexpression induced collagen deposition and up-regulated the expression of α-SMA and p-Smad2/3, and AdshSmad3 inhibited IGFBPrP1-stimulated p-Smad2/3 activation and the expression of α-SMA, collagen I and fibronectin in HSC-T6 cells. Similarly, increased hepatocyte apoptosis (38.56% ± 3.42% vs 0.24% ± 0.03%, P < 0.05), α-SMA positive stained cells (29.84% ± 1.36% vs 5.83% ± 1.47%, P < 0.05), and increased numbers of Smad3 (35.88% ± 2.15% vs 10.24% ± 1.31%, P < 0.05) and p-Smad2/3 positive cells (28.87% ± 2.73% vs 8.23% ± 0.98%, P < 0.05) were detected in the livers of IGFBPrP1-overexpressing rats compared with the control group. Moreover, AdshSmad3 reduced IGFBPrP1-stimulated Smad3 expression and attenuated α-SMA expression (29.84% ± 1.36% vs 8.23% ± 1.28%, P < 0.05), hepatocyte apoptosis (38.56% ± 3.42% vs 6.75% ± 0.52%, P < 0.05), and both collagen I and fibronectin deposition in the livers of AdIGFBPrP1-treated rats.

CONCLUSION

IGFBPrP1 induces liver fibrosis by mediating the activation of hepatic stellate cells and hepatocyte apoptosis in a Smad3-dependent mechanism.

Authors+Show Affiliations

Yun Zhang, Department of Gastroenterology and Hepatology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.Yun Zhang, Department of Gastroenterology and Hepatology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.Yun Zhang, Department of Gastroenterology and Hepatology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.Yun Zhang, Department of Gastroenterology and Hepatology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.Yun Zhang, Department of Gastroenterology and Hepatology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24914373

Citation

Zhang, Yun, et al. "IGFBPrP1 Induces Liver Fibrosis By Inducing Hepatic Stellate Cell Activation and Hepatocyte Apoptosis Via Smad2/3 Signaling." World Journal of Gastroenterology, vol. 20, no. 21, 2014, pp. 6523-33.
Zhang Y, Zhang QQ, Guo XH, et al. IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling. World J Gastroenterol. 2014;20(21):6523-33.
Zhang, Y., Zhang, Q. Q., Guo, X. H., Zhang, H. Y., & Liu, L. X. (2014). IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling. World Journal of Gastroenterology, 20(21), 6523-33. https://doi.org/10.3748/wjg.v20.i21.6523
Zhang Y, et al. IGFBPrP1 Induces Liver Fibrosis By Inducing Hepatic Stellate Cell Activation and Hepatocyte Apoptosis Via Smad2/3 Signaling. World J Gastroenterol. 2014 Jun 7;20(21):6523-33. PubMed PMID: 24914373.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling. AU - Zhang,Yun, AU - Zhang,Qian-Qian, AU - Guo,Xiao-Hong, AU - Zhang,Hai-Yan, AU - Liu,Li-Xin, PY - 2013/11/11/received PY - 2014/01/14/revised PY - 2014/02/20/accepted PY - 2014/6/11/entrez PY - 2014/6/11/pubmed PY - 2015/4/14/medline KW - Hepatic stellate cells KW - Hepatocyte apoptosis KW - Insulin-like growth factor binding protein-related protein 1 KW - Liver fibrosis KW - Smad pathway SP - 6523 EP - 33 JF - World journal of gastroenterology JO - World J. Gastroenterol. VL - 20 IS - 21 N2 - AIM: To investigate the role and mechanism of insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) in the development of liver fibrosis. METHODS: An in vitro model using hepatic stellate cell (HSC)-T6 cells and an in vivo model of rat liver overexpressing IGFBPrP1 were established using an IGFBPrP1-expressing recombinant adenovirus. The expression of IGFBPrP1 was examined by immunofluorescence, and the expression of collagen I and fibronectin was measured by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The expression of Smad2/3 and p-Smad2/3 was examined by Western blot and immunohistochemistry. A shSmad3-expressing recombinant adenovirus (AdshSmad3) was designed and used to knockdown the Smad3 gene in HSC-T6 cells and rat liver fibrosis transfected with IGFBPrP1. The expression of collagen I, fibronectin, and α-smooth muscle actin (α-SMA) was determined by Western blot analysis and immunohistochemistry. Hepatocyte apoptosis was assessed using TUNEL assay. RESULTS: IGFBPrP1 overexpression induced collagen deposition and up-regulated the expression of α-SMA and p-Smad2/3, and AdshSmad3 inhibited IGFBPrP1-stimulated p-Smad2/3 activation and the expression of α-SMA, collagen I and fibronectin in HSC-T6 cells. Similarly, increased hepatocyte apoptosis (38.56% ± 3.42% vs 0.24% ± 0.03%, P < 0.05), α-SMA positive stained cells (29.84% ± 1.36% vs 5.83% ± 1.47%, P < 0.05), and increased numbers of Smad3 (35.88% ± 2.15% vs 10.24% ± 1.31%, P < 0.05) and p-Smad2/3 positive cells (28.87% ± 2.73% vs 8.23% ± 0.98%, P < 0.05) were detected in the livers of IGFBPrP1-overexpressing rats compared with the control group. Moreover, AdshSmad3 reduced IGFBPrP1-stimulated Smad3 expression and attenuated α-SMA expression (29.84% ± 1.36% vs 8.23% ± 1.28%, P < 0.05), hepatocyte apoptosis (38.56% ± 3.42% vs 6.75% ± 0.52%, P < 0.05), and both collagen I and fibronectin deposition in the livers of AdIGFBPrP1-treated rats. CONCLUSION: IGFBPrP1 induces liver fibrosis by mediating the activation of hepatic stellate cells and hepatocyte apoptosis in a Smad3-dependent mechanism. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/24914373/IGFBPrP1_induces_liver_fibrosis_by_inducing_hepatic_stellate_cell_activation_and_hepatocyte_apoptosis_via_Smad2/3_signaling_ L2 - http://www.wjgnet.com/1007-9327/full/v20/i21/6523.htm DB - PRIME DP - Unbound Medicine ER -